Substituted phenylmethyl bicyclocarboxyamide compounds

ABSTRACT

This invention provides a compound of the formula (I). These compounds are useful for the treatment of disease conditions caused by overactivation of the VR1 receptor such as pain, or the like in mammal. This invention also provides a pharmaceutical composition comprising the above compound.

TECHNICAL FIELD

This invention relates to novel substituted phenylmethylbicyclocarboxamide compounds and to their use in therapy. Thesecompounds are particularly useful as modulators of the VR1 (Type IVanilloid) receptor, and are thus useful for the treatment of diseasessuch as pain, neuralgia, neuropathies, nerve injury, burns, migraine,carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvichypersensitivity, bladder disease, inflammation, or the like in mammals,especially humans. The present invention also relates to apharmaceutical composition comprising the above compounds.

BACKGROUND ART

The Vanilloid receptor 1 (VR1) is a ligand gated non-selective cationchannel. It is believed to be a member of the transient receptorpotential super family. VR1 is recognized as a polymodal nociceptor thatintegrates multiple pain stimuli, e.g., noxious heat, protons, andvanilloids (European Journal of Physiology 451:151-159, 2005). A majordistribution of VR1 is in the sensory (Aδ- and C-) fibres, which arebipolar neurons having somata in sensory ganglia. The peripheral fibresof these neurons innervate the skin, the mucosal membranes, and almostall internal organs. It is also recognized that VR1 exists in bladder,kidney, brain, pancreas, and various kinds of organs. A body of studiesusing VR1 agonists, e.g., capsaicin or resiniferatoxin, have suggestedthat VR1 positive nerves are thought to participate in a variety ofphysiological responses, including nociception (Clinical Therapeutics.13(3): 338-395, 1991, Journal of Pharmacology and ExperimentalTherapeutics 314:410-421, 2005, and Neuroscience Letter 388: 75-80,2005). Based on both the tissue distribution and the roles of VR1, VR1antagonists would have good therapeutic potential.

WO2005070929 discloses heterocyclic amine derivatives as vanilloidreceptor ligands. WO2005070885 discloses amide derivatives useful asvanilloid receptor ligands. WO2005003084 discusses4-(methylsulfonylamino)phenyl analogues which are stated to haveactivity as VR1 antagonists. WO 2004069792 discloses quinoline-derivedamide derivatives useful for prevention or treatment of e.g.inflammatory pain, burning pain, chronic obstructive pulmonary diseaseand osteoarthritis, are vanilloid receptor 1 modulators. WO 2003080578discloses heteroaromatic urea derivatives are vanilloid-1 receptormodulators used for treating diseases and conditions in which painand/or inflammation predominates. WO 2003068749 discloses quinoline orisoquinoline carboxamide derivatives useful as antagonist of thevanilloid receptor (VR1). WO 2003014064 discloses amide derivativesuseful as vanilloid receptor 1 antagonists. WO 2002100819 disclosesN-arylphenylacetamide derivatives as vanilloid receptor VR1 antagonistsfor e.g. treating pain, mania and allergic rhinitis. WO2006051378discloses a variety of N-sulfonylaminobenzyl-2-phenoxy amide derivativesas modulator of the vanilloid receptor. JP11080107 discloses amidecompounds as bone formation promoters for use as antiosteoporoticagents. WO2005033079 discloses heterocyclic derivatives, useful fortreating fungal infections. WO03035621 discloses naphthyl amidecompounds as protein kinase and phosphatase inhibitors for treating e.g.diabetes, obesity and hearing loss.

It is desirable to provide new VR1 selective antagonist with potentbinding activity and good metabolic stability. Other potentialadvantages include low toxicity, good absorption, good solubility, lowprotein binding affinity, low drug-drug interaction, a reducedinhibitory activity at HERG channel and reduced QT prolongation.

BRIEF DISCLOSURE OF THE INVENTION

It has now been found that certain substituted carboxamide derivativesare potent VR1 antagonists with analgesic activity by systemicadministration.

The present invention provides a compound of the following formula (I):

wherein

-   Y¹ and Y² are each independently CH or N, Y³ is CR⁸ or N, with the    proviso that only one of Y¹, Y² and Y³ is N;-   R¹ and R² are each independently hydrogen, (C₁-C₆)alkyl,    halo(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl;-   R³ is hydrogen, halogen, hydroxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,    hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkyl,    (C₁-C₆)alkoxy-(C₁-C₆)alkoxy or halo(C₁-C₆)alkyl;-   R⁴ is halogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₁-C₆)alkyl,    hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy,    (C₁-C₆)alkoxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy,    halo(C₁-C₆)alkylsulfonyl, halo(C₁-C₆)alkylsulfinyl,    halo(C₁-C₆)alkylthio, [(C₁-C₆)alkyl]NH—, [(C₁-C₆)alkyl]₂N—,    azetidinyl, pyrrolidinyl or piperidinyl;-   R⁶ is hydroxy, hydroxy(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;-   R⁵ is hydrogen, halogen, hydroxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,    or (C₁-C₆)alkoxy;-   R⁷ is hydrogen, halogen, hydroxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,    or (C₁-C₆)alkoxy;-   R⁸ is hydrogen, halogen, (C₁-C₆)alkyl, or halo(C₁-C₆)alkyl;-   or a pharmaceutically acceptable salt or solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “halogen” means fluoro, chloro, bromo or iodo,preferably fluoro or chloro.

As used herein, the terms “(C₁-C₆)alkyl” and “(C₁-C₄)alkyl” meanstraight or branched chain saturated radicals having the required numberof carbon atoms, including, but not limited to methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, secondary-butyl, tert-butyl and2-methylbutyl groups. Preferred groups are methyl, ethyl, n-propyl,n-butyl, tert-butyl and 2-methylbutyl groups.

As used herein, the terms “(C₃-C₆)cycloalkyl” means non-aromaticsaturated or unsaturated hydrocarbon ring, having the required number ofcarbon atoms, including, but not limited to cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl groups.

As used herein, the term “(C₁-C₆)alkoxy” means (C₁-C₆)alkyl-O— wherein(C₁-C₆)alkyl radical is as defined above, including, but not limited tomethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy and tert-butoxy. Preferred groups are methoxy, ethoxy,n-propoxy, n-butoxy and tert-butoxy.

As used herein, the term “hydroxy(C₁-C₆)alkyl” means (C₁-C₆)alkylradical as defined above which is substituted by at least one hydroxygroup including, but not limited to, hydroxymethyl, hydroxyethyl,hydroxy n-propyl, hydroxy iso-propyl (e. g.1-hydroxy-1,1-dimethylmethyl), hydroxy n-butyl, hydroxy iso-butyl,hydroxy secondary-butyl and hydroxy tert-butyl. Preferred groups arehydroxymethyl, hydroxyethyl, hydroxy n-propyl, hydroxy iso-propyl (e. g.1-hydroxy-1,1-dimethylmethyl), hydroxy n-butyl and hydroxy tent-butyl.

As used herein, the term “hydroxy(C₁-C₆)alkoxy” means (C₁-C₆)alkoxyradical as defined above which is substituted by hydroxy groupincluding, but not limited to, hydroxymethoxy, hydroxyethoxy, hydroxyn-propoxy, hydroxy iso-propoxy, hydroxy n-butoxy, hydroxy iso-butoxy,hydroxy sec-butoxy and hydroxy tert-butoxy. Preferred hydroxyalkoxygroups are hydroxymethoxy, hydroxyethoxy, hydroxy n-propoxy and hydroxyn-butoxy.

As used herein, the term “(C₁-C₆)alkoxy-(C₁-C₆)alkyl” means (C₁-C₆)alkylradical as defined above which is substituted by (C₁-C₆)alkoxy group asdefined above.

As used herein, the term “(C₁-C₆)alkoxy-(C₁-C₆)alkoxy” means(C₁-C₆)alkoxy radical as defined above which is substituted by(C₁-C₆)alkoxy as defined above. Preferred groups are methoxy methoxy,methoxy ethoxy or ethoxy ethoxy groups.

As used herein, the term “hydroxy(C₁-C₆)alkoxy-(C₁-C₆)alkyl” means(C₁-C₆)alkyl radical as defined above which is substituted byhydroxy(C₁-C₆)alkoxy group or radical as defined above which issubstituted by hydroxy(C₁-C₄)alkoxy group as defined above.

As used herein the term “halo(C₁-C₆)alkyl” and “halo(C₁-C₄)alkyl” mean(C₁-C₆)alkyl or (C₁-C₄)alkyl radical which is substituted by one or morehalogen atoms as defined above including, but not limited to,fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl,2,2,2-trifluoro-1,1-dimethylethyl, 2,2,2-trichloroethyl, 3-fluoropropyl,4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl, bromomethyland 4,4,4-trifluoro-3-methylbutyl groups. Preferred groups arefluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl and2,2,2-trifluoro-1,1-dimethylethyl groups.

As used herein the terms “halo(C₁-C₆)alkoxy” mean (C₁-C₆)alkyl-O—, whichis substituted by one or more halogen atoms as defined above including,but not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,2,2,2-trifluoro-1,1-dimethylethoxy, 2,2,2-trichloroethoxy,3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy,iodomethoxy, bromomethoxy and 4,4,4-trifluoro-3-methylbutoxy groups.Preferred halo(C₁-C₆)alkyl-O— or halo(C₁-C₃)alkyl-O— groups arefluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and2,2,2-trifluoro-1,1-dimethylethoxy groups.

As used herein, the terms “(C₁-C₆)alkylthio” means (C₁-C₆)alkyl-S—wherein (C₁-C₆)alkyl radical is as defined above, including, but notlimited to methylthio, ethylthio, propylthio and butylthio. Preferredgroups are methylthio and ethylthio groups.

As used herein, the terms “(C₁-C₆)alkylsulfinyl” means (C₁-C₆)alkyl-SO—wherein (C₁-C₆)alkyl radical is as defined above, including, but notlimited to methylsulfinyl, ethylsulfinyl, propylsulfinyl andbutylsulfinyl. Preferred groups are methylsulfinyl and ethylsulfinylgroups.

As used herein, the terms “(C₁-C₆)alkylsulfonyl” means (C₁-C₆)alkyl-SO₂—wherein (C₁-C₆)alkyl radical is as defined above, including, but notlimited to methylsulfonyl, ethylsulfonyl, propylsulfonyl andbutylsulfonyl. Preferred groups are methylsulfonyl and ethylsulfonylgroups.

As used herein, the terms “halo(C₁-C₆)alkylthio” means (C₁-C₆)alkyl-S—,which is substituted by one or more halogen atoms as defined above,including, but not limited to fluoromethylthio, difluoromethylthio,trifluoromethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio,2,2,2-trifluoroethylthio, 2,2,2-trifluoro-1,1-dimethylethylthio,2,2,2-trichloroethylthio, 3-fluoropropylthio, 4-fluorobutylthio,chloromethylthio, trichloromethylthio, iodomethylthio, bromomethylthioand 4,4,4-trifluoro-3-methylbutylthio groups. Preferred groups arefluoromethylthio, difluoromethylthio, trifluoromethylthio,2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio and2,2,2-trifluoro-1,1-dimethylethylthio groups.

As used herein, the terms “halo(C₁-C₆)alkylsulfinyl” means(C₁-C₆)alkyl-SO—, which is substituted by one or more halogen atoms asdefined above, including, but not limited to fluoromethylsulfinyl,difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl,2,2-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,2,2,2-trifluoro-1,1-dimethylethylsulfinyl, 2,2,2-trichloroethylsulfinyl,3-fluoropropylsulfinyl, 4-fluorobutylsulfinyl, chloromethylsulfinyl,trichloromethylsulfinyl, iodomethylsulfinyl, bromomethylsulfinyl and4,4,4-trifluoro-3-methylbutylsulfinyl groups. Preferred groups arefluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl,2-fluoroethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl and2,2,2-trifluoro-1,1-dimethylethylsulfinyl groups.

As used herein, the terms “halo(C₁-C₆)alkylsulfonyl” means(C₁-C₆)alkyl-SO₂—, which is substituted by one or more halogen atoms asdefined above, including, but not limited to fluoromethylsulfonyl,difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl,2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2,2-trifluoro-1,1-dimethylethylsulfonyl, 2,2,2-trichloroethylsulfonyl,3-fluoropropylsulfonyl, 4-fluorobutylsulfonyl, chloromethylsulfonyl,trichloromethylsulfonyl, iodomethylsulfonyl, bromomethylsulfonyl and4,4,4-trifluoro-3-methylbutylsulfonyl groups. Preferred groups arefluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl,2-fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl,2,2,2-trifluoroethylsulfonyl and2,2,2-trifluoro-1,1-dimethylethylsulfonyl groups.

As used herein, the term “[(C₁-C₆)alkyl]NH—” means alkyl-NH— whereinalkyl is defined above, including, but not limited to methylamino,ethylamino, n-propylamino, iso-propylamino, n-butylamino,iso-butylamino, secondary-butylamino, tert-butylamino. Preferredalkylamino groups are methylamino, ethylamino, n-propylamino, andn-butylamino.

As used herein, the term “[(C₁-C₆)alkyl]₂N—” means dialkyl-N— whereinalkyl is defined above, including, but not limited to dimethylamino,diethylamino, methylethylamino, di n-propylamino, methyl n-propylamino,ethyl n-propylamino diiso-propylamino, di n-butylamino, methyln-butylamino di iso-butylamino, di secondary-butylamino, ditert-butylamino. Preferred dialkylamino groups are dimethylamino,diethylamino, di n-propylamino, di n-butylamino.

Preferred structures of the formula (I) include as follows:

-   -   Preferably, R⁸ is H.    -   Preferably, Y¹ is CH, Y² is CH and Y³ is CH.    -   Preferably, Y¹ is N, Y² is CH and Y³ is CH.    -   Preferably, Y¹ is CH, Y² is N and Y³ is CH.    -   Preferably, Y¹ is CH, Y² is CH and Y³ is N.    -   Preferably, R¹ and R² are each independently hydrogen or        (C₁-C₆)alkyl, preferably methyl. More preferably, R¹ is hydrogen        or methyl and R² is hydrogen. More preferably, R¹ is methyl and        R² is hydrogen.    -   Preferably, when R¹ is not hydrogen and R² is hydrogen, then the        carbon atom bearing R¹ and R² is in the (R) configuration.    -   Preferably, R³ is hydrogen, halogen, or C₁-C₄ alkyl. More        preferably R³ is hydrogen.    -   Preferably, R⁴ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl. More        preferably, R⁴ is tert-butyl, trifluoromethyl or        2,2,2-trifluoro-1,1-dimethyl-ethyl.    -   Preferably, R⁶ is hydroxy, hydroxymethyl or methoxy.    -   Preferably, R⁵ is hydrogen, halogen, hydroxy, (C₁-C₆)alkyl or        (C₁-C₆)alkoxy. More preferably, R⁵ is hydrogen, (C₁-C₆)alkyl or        (C₁-C₆)alkoxy. More preferably, R⁵ is hydrogen, methyl or        methoxy.    -   Preferably, R⁷ is hydrogen, halogen, hydroxy, (C₁-C₆)alkyl or        (C₁-C₆)alkoxy. More preferably, R⁷ is hydrogen or halogen. More        preferably, R⁷ is hydrogen, fluoro, chloro or bromo.    -   Preferably, R⁵ is methyl, R⁶ is CH₂OH, hydroxy or methoxy and R⁷        is chloro, fluoro or bromo.    -   Preferably, R⁵ is methyl, R⁶ is hydroxy or methoxy and R⁷ is        chloro.    -   Preferably, R⁵ is methoxy, R⁶ is hydroxy and R⁷ is chloro,        fluoro or bromo.    -   Preferably, R⁵ is methoxy, R⁶ is hydroxy and R⁷ is chloro.    -   Preferably, R⁵ is hydrogen, R⁶ is —CH₂OH and R⁷ is hydrogen.    -   Preferably, R⁵ is methoxy, R⁶ is hydroxy and R⁷ is hydrogen.

Preferred compounds of the invention include those in which eachvariable in formula (I) is selected from the preferred groups for eachvariable.

Specific preferred compounds of the invention are those listed in theExamples section below and the pharmaceutically acceptable salts andsolvates thereof.

The compounds of formula (I), being VR1 antagonists, are potentiallyuseful in the treatment of a range of disorders, particularly thetreatment of pain, including chronic pain, acute pain, nociceptive pain,neuropathic pain, inflammatory pain, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns,back pain, visceral pain, cancer pain, dental pain, headache, migraine,carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvichypersensitivity, pelvic pain and menstrual pain; bladder disease, suchas urinary incontinence, lower urinary tract symptoms, micturitiondisorder, renal colic and cystitis; inflammation, such as burns,rheumatoid arthritis and osteoarthritis; neurodegenerative disease, suchas stroke, post stroke pain and multiple sclerosis; diseases of therespiratory tree that have a contribution to symptoms or pathologyarising from the sensory afferent nervous system, such as cough,bronchoconstriction, irritation, inflammation and other pathways indiseases of the lower airway such as asthma and chronic obstructivepulmonary disease (COPD) as well as those of the upper airway, such asallergic rhinitis and chronic sinusitis; gastrointestinal disorders,such as gastroesophageal reflux disease (GERD), dysphagia, ulcer,irritable bowel syndrome (IBS), inflammatory bowel disease (IBD),colitis and Crohn's disease; ischemia, such as cerebrovascular ischemiaand acute cerebral ischemia; emesis, such as cancer chemotherapy-inducedemesis; diabetes and obesity, or the like in mammals, especially humans.The treatment of pain is a preferred use, particularly inflammatory pain

Physiological pain is an important protective mechanism designed to warnof danger from potentially injurious stimuli from the externalenvironment. The system operates through a specific set of primarysensory neurones and is activated by noxious stimuli via peripheraltransducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164for a review). These sensory fibres are known as nociceptors and arecharacteristically small diameter axons with slow conduction velocities.Nociceptors encode the intensity, duration and quality of noxiousstimulus and by virtue of their topographically organised projection tothe spinal cord, the location of the stimulus. The nociceptors are foundon nociceptive nerve fibres of which there are two main types, A-deltafibres (myelinated) and C fibres (non-myelinated). The activitygenerated by nociceptor input is transferred, after complex processingin the dorsal horn, either directly, or via brain stem relay nuclei, tothe ventrobasal thalamus and then on to the cortex, where the sensationof pain is generated.

Pain may generally be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological' response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain are neuropathic pain (e.g. painful diabetic neuropathy,postherpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma,the characteristics of nociceptor activation are altered and there issensitisation in the periphery, locally around the injury and centrallywhere the nociceptors terminate. These effects lead to a heightenedsensation of pain. In acute pain these mechanisms can be useful, inpromoting protective behaviours which may better enable repair processesto take place. The normal expectation would be that sensitivity returnsto normal once the injury has healed. However, in many chronic painstates, the hypersensitivity far outlasts the healing process and isoften due to nervous system injury. This injury often leads toabnormalities in sensory nerve fibres associated with maladaptationand'aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivityfeature among the patient's symptoms. Patients tend to be quiteheterogeneous and may present with various pain symptoms. Such symptomsinclude: 1) spontaneous pain which may be dull, burning, or stabbing; 2)exaggerated pain responses to noxious stimuli (hyperalgesia); and 3)pain produced by normally innocuous stimuli (allodynia—Meyer et al.,1994, Textbook of Pain, 13-44). Although patients suffering from variousforms of acute and chronic pain may have similar symptoms, theunderlying mechanisms may be different and may, therefore, requiredifferent treatment strategies. Pain can also therefore be divided intoa number of different subtypes according to differing pathophysiology,including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli withthe potential to cause injury. Pain afferents are activated bytransduction of stimuli by nociceptors at the site of injury andactivate neurons in the spinal cord at the level of their termination.This is then relayed up the spinal tracts to the brain where pain isperceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activationof nociceptors activates two types of afferent nerve fibres. MyelinatedA-delta fibres transmit rapidly and are responsible for sharp andstabbing pain sensations, whilst unmyelinated C fibres transmit at aslower rate and convey a dull or aching pain. Moderate to severe acutenociceptive pain is a prominent feature of pain from central nervoussystem trauma, strains/sprains, burns, myocardial infarction and acutepancreatitis, post-operative pain (pain following any type of surgicalprocedure), posttraumatic pain, renal colic, cancer pain and back pain.Cancer pain may be chronic pain such as tumour related pain (e.g. bonepain, headache, facial pain or visceral pain) or pain associated withcancer therapy (e.g. postchemotherapy syndrome, chronic postsurgicalpain syndrome or post radiation syndrome). Cancer pain may also occur inresponse to chemotherapy, immunotherapy, hormonal therapy orradiotherapy. Back pain may be due to herniated or rupturedintervertabral discs or abnormalities of the lumber facet joints,sacroiliac joints, paraspinal muscles or the posterior longitudinalligament. Back pain may resolve naturally but in some patients, where itlasts over 12 weeks, it becomes a chronic condition which can beparticularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by aprimary lesion or dysfunction in the nervous system. Nerve damage can becaused by trauma and disease and thus the term ‘neuropathic pain’encompasses many disorders with diverse aetiologies. These include, butare not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy,HIV neuropathy, phantom limb pain, carpal tunnel syndrome, centralpost-stroke pain and pain associated with chronic alcoholism,hypothyroidism, uremia, multiple sclerosis, spinal cord injury,Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic painis pathological as it has no protective role. It is often present wellafter the original cause has dissipated, commonly lasting for years,significantly decreasing a patient's quality of life (Woolf and Mannion,1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain aredifficult to treat, as they are often heterogeneous even betweenpatients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6,S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Theyinclude spontaneous pain, which can be continuous, and paroxysmal orabnormal evoked pain, such as hyperalgesia (increased sensitivity to anoxious stimulus) and allodynia (sensitivity to a normally innocuousstimulus).

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most commoninflammatory pain. Rheumatoid disease is one of the commonest chronicinflammatory conditions in developed countries and rheumatoid arthritisis a common cause of disability. The exact aetiology of rheumatoidarthritis is unknown, but current hypotheses suggest that both geneticand microbiological factors may be important (Grennan & Jayson, 1994,Textbook of Pain, 397-407). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook ofPain, 387-395). Most patients with osteoarthritis seek medical attentionbecause of the associated pain. Arthritis has a significant impact onpsychosocial and physical function and is known to be the leading causeof disability in later life. Ankylosing spondylitis is also a rheumaticdisease that causes arthritis of the spine and sacroiliac joints. Itvaries from intermittent episodes of back pain that occur throughoutlife to a severe chronic disease that attacks the spine, peripheraljoints and other body organs.

Another type of inflammatory pain is visceral pain which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain. Commonlyencountered gastrointestinal (GI) disorders that cause pain includesfunctional bowel disorder (FBD) and inflammatory bowel disease (IBD).These GI disorders include a wide range of disease states that arecurrently only moderately controlled, including, in respect of FBD,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) andfunctional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Other types of visceral pain include the painassociated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies andthus can be classified in more than one area, e.g. back pain and cancerpain have both nociceptive and neuropathic components.

Other types of pain include:

-   -   pain resulting from musculo-skeletal disorders, including        myalgia, fibromyalgia, spondylitis, sero-negative        (non-rheumatoid) arthropathies, non-articular rheumatism,        dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;    -   heart and vascular pain, including pain caused by angina,        myocardical infarction, mitral stenosis, pericarditis, Raynaud's        phenomenon, scleredoma and skeletal muscle ischemia;    -   head pain, such as migraine (including migraine with aura and        migraine without aura), cluster headache, tension-type headache        mixed headache and headache associated with vascular disorders;        and    -   orofacial pain, including dental pain, otic pain, burning mouth        syndrome and temporomandibular myofascial pain.

Urinary incontinence (any condition in which there is an involuntaryleakage of urine), includes stress urinary incontinence, urge urinaryincontinence and mixed urinary incontinence, overactive bladder withassociated urinary incontinence, enuresis, nocturnal enuresis,continuous urinary incontinence, and situational urinary incontinencesuch as incontinence during sexual intercourse.

Lower urinary tract symptoms comprise three groups of urinary symptoms,which may be defined as storage (irritative), voiding (obstructive) andpost-micturition symptoms. Storage symptoms comprise urgency, frequency,nocturia, urgency incontinence and stress incontinence, which can beassociated with overactive bladder (OAB) and benign prostatichyperplasia (BPH). Voiding symptoms comprise hesitancy, poor flow,intermittency, straining and dysuria. Post-micturition symptoms compriseterminal dribbling, post-void dribbling and a sense of incompleteemptying.

Over Active Bladder (OAB) is defined as urgency, with or without urgeincontinence, usually with frequency and nocturia [Abrams et al.,Neurourology and Urodynamics 21:167-178 (2002)]. Prevalence of OAB inmen and women is similar, with approximately 16% of the population ofthe USA suffering from the condition [Stewart et al, Prevalence ofOveractive Bladder in the United States: Results from the NOBLE Program;Abstract Presented at the 2^(nd) International Consultation onIncontinence, July 2001, Paris, France]. OAB includes OAB Wet and OABDry. The terms OAB Wet and OAB Dry describe OAB patients with or withouturinary incontinence, respectively. Until recently, the cardinal symptomof OAB was believed to be urinary incontinence. However, with the adventof the new terms this is clearly not meaningful for the large number ofsufferers who are not incontinent (i.e. OAB Dry patients). Thus, arecent study from Liberman et al ['Health Related Quality of Life AmongAdults with Symptoms of Overactive Bladder: Results From A USCommunity-Based Survey'; Urology 57(6), 1044-1050, 2001] examined theimpact of all OAB symptoms on the quality of life of a community-basedsample of the US population. This study demonstrated that individualssuffering from OAB without any demonstrable loss of urine have animpaired quality of life when compared with controls.

BPH is a chronically progressive disease that can lead to complicationssuch as acute urinary retention, recurrent urinary tract infections,bladder stones and renal dysfunction. The prevalence and averageseverity of LUTS associated with BPH in men increases with age. BPHleads to an increase in prostate volume, creating urethral and bladderoutflow obstruction as well as secondary changes in bladder function.The effects of this are manifested by both storage (irritative) andvoiding (obstructive) symptoms.

The present invention provides a pharmaceutical composition including acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, together with a pharmaceutically acceptable excipient.The composition is preferably useful for the treatment of the diseaseconditions defined above.

The present invention further provides a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, for use as amedicament. The present invention further provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for usein the treatment of a disease condition defined above.

Further, the present invention provides a method for the treatment ofthe disease conditions defined above in a mammal, preferably a human,which includes administering to said mammal a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof.

Yet further, the present invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,in the manufacture of a medicament for the treatment of the diseaseconditions defined above.

Yet further, the present invention provides a combination of a compoundof the formula (I), or a pharmaceutically acceptable salt or solvatethereof, and another pharmacologically active agent.

In this specification, especially in “General Synthesis” and “Examples”,the following abbreviations can be used:

-   BEP 2-bromo-1-ethylpyridinium tetrafluoroborate-   BOP benzotriazol-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate-   CDI 2-chloro-1,3-dimethylimidazolinium chloride-   DCC dicyclohexylcarbodiimide-   DCM dichloromethane-   DME 1,2-dimethoxyethane, dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EDC 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrogen chloride-   Et₂O diethylether-   EtOAc ethyl acetate-   EtOH ethanol-   HBTU 2-(1H-benzenotriasol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxybenzotriazole-   Me methyl-   MeOH methanol-   NMP N-methyl-2-pyrroliidone-   THF tetrahydrofuran-   TFA trifluoroacetic acid-   TMS trimethyl silane

General Synthesis

This illustrates the preparation of compounds of formula (I).

Step 1A: In this Step, amide compounds of formula (I) can be prepared bythe coupling reaction of an amine compound of formula (II) with an acidcompound of formula (III) in the presence or absence of a couplingreagent in an inert solvent. Suitable coupling reagents are thosetypically used in peptide synthesis including, for example, diimides(e.g., DCC, EDC, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, BEP,CDI, BOP, diethyl azodicarboxylate-triphenylphosphine,diethylcyanophosphate, diethylphosphorylazide,2-chloro-1-methylpyridinium iodide, N,N′-carbonyldiimidazole,benzotriazole-1-yl diethyl phosphate, ethyl chloroformate or isobutylchloroformate). The reaction can be carried out in the presence of abase such as HOBt, N,N-diisopropylethylamine, N-methylmorpholine ortriethylamine. The amide compound of formula (I) can be formed via anacylhalide, which can be obtained by the reaction with halogenatingagents such as oxalylchloride, phosphorus oxychloride or thionylchloride. The reaction is normally and preferably carried out in thepresence of a solvent. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solvents includeacetone; nitromethane; N,N-dimethylformamide; NMP; sulfolane; dimethylsulfoxide; 2-butanone; acetonitrile; halogenated hydrocarbons suchas dichloromethane, dichloroethane or chloroform; and ethers such as THFor 1,4-dioxane. The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. The preferred reaction temperature will depend upon suchfactors as the nature of the solvent, and the starting material orreagent used. However, in general, we find it convenient to carry outthe reaction at a temperature of from −20° C. to 100° C., morepreferably from about 0° C. to 60° C. The time required for the reactioncan also vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents and solvent employed.

However, provided that the reaction is effected under the preferredconditions outlined above, a period of 5 minutes to 1 week, morepreferably 30 minutes to 24 hours, will usually suffice.

Scheme 2:

When R⁶ is hydroxy, a compound of formula (I) may be prepared from acorresponding alkoxy compound of formula (I) by dealkylation, asillustrated by the following process, wherein R′ is (C₁-C₆)alkyl.

Step-2A

In this Step, a compound of formula (I') can be prepared by dealkylationof a compound of formula (I) with a dealkylating agent in an inertsolvent. Examples of suitable dealkylating agents include: boron halidessuch as boron tribromide or boron trichloride; and hydrogen halides,such as hydrogen bromide. Preferred reaction inert solvents include, forexample: halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform or carbon tetrachloride; and acetic acid.Reaction temperatures are generally in the range of from −100 to 200°C., preferably in the range of from −80° C. to 80° C. Reaction timesare, in general, from 1 minute to a day, preferably from 1 hour to 10hours.

The amine of formula (II) can be easily prepared by the man skilled inthe art. Schemes 3 to 8 represents generic processes useful for thepreparation of compounds of formula (II).

Scheme 3:

wherein, M is a methal, such as lithium, or a metal halide, such as MgZwherein Z is a halogen; and

L is a suitable leaving group;

Step 3A: In this Step, a compound of formula (IIc) may be prepared byreacting a compound of formula (IIb) with carbon monoxide and alcohol(e.g. MeOH, EtOH) in the presence of a catalyst and/or base in an inertsolvent. Examples of suitable catalysts include: palladium reagents,such as palladium acetate or palladium dibenzylacetone. Examples ofsuitable bases include N,N-diisopropylethylamine, N-methylmorpholine ortriethylamine. If desired, this reaction may be carried out in thepresence or absence of an additive such as1,1′-bis(diphenylphosphino)ferrocene, triphenylphosphine or1,3-bis-(diphenylphosphino)propane (DPPP). The reaction is normally andpreferably effected in the presence of a solvent. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or on the reagents involved andthat it can dissolve the reagents, at least to some extent.

Examples of suitable solvents include acetone; nitromethane; DMF;sulfolane; DMSO; NMP; 2-butanone; acetonitrile; halogenated hydrocarbonssuch as DCM, dichloroethane or chloroform; or ethers, such as THF or1,4-dioxane. The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. The preferred reaction temperature will depend upon suchfactors as the nature of the solvent, and the starting material orreagent used. However, in general, we find it convenient to carry outthe reaction at a temperature of from −20° C. to 150° C., morepreferably from about 50° C., to 80° C. The time required for thereaction may also vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents and solventemployed. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of 30 minutes to 24 hours,more preferably 1 hour to 10 hours, will usually suffice.

Step 3B-1: In this Step, an acid compound may be prepared by hydrolysisof the compound of formula (IIc) in a solvent. The hydrolysis may becarried out by conventional procedures. In a typical procedure, thehydrolysis is carried out under the basic condition in the presence ofwater, suitable bases include, for examples, sodium hydroxide, potassiumhydroxide or lithium hydroxide. Suitable solvents include, for example,alcohols such as MeOH, EtOH, propanol, butanol, 2-methoxyethanol orethylene gylcol; ethers such as THF, DME or 1,4-dioxane; amides such asDMF or hexamethylphosphorictriamide; or sulfoxides such as DMSO. Thisreaction may be carried out at a temperature in the range from −20 to100° C., usually from 20° C. to 65° C. for 30 minutes to 24 hours,usually 60 minutes to 10 hours. The hydrolysis may also be carried outunder acidic conditions, e.g. in the presence of hydrogen halides suchas hydrogen chloride and hydrogen bromide; sulfonic acids such asp-toluenesulfonic acid and benzenesulfonic acid; pyridiump-toluenesulfonate; and carboxylic acids such as acetic acid andtrifluoroacetic acid. Suitable solvents include, for example, alcoholssuch as MeOH, EtOH, propanol, butanol, 2-methoxyethanol, and ethylenegylcol; ethers such as THF, DME and 1,4-dioxane; amides such as DMF andhexamethylphosphorictriamide; and sulfoxides such as DMSO. This reactionmay be carried out at a temperature in the range from −20 to 100° C.,usually from 20° C. to 65° C. for 30 minutes to 24 hours, usually 60minutes to 10 hours.

Step 3B-2: In this step, an amide compound of formula (IIb) can beprepared from a compound of 3B-1 by the same procedure as Step 1A.

Step 3C: In this Step, a compound of formula (IIa) can be prepared byreaction of a compound of formula (IIb) with an organometallic reagentR²M. R²M can be prepared by reaction of a halide compound of R². Forexample, R²M, in which M represents MgZ, can be generated with stirringMg and R²Z, dibromoethane and 1₂ at a temperature in the range ofbetween 30-80° C. This reaction may be carried out in the presence of anorganometallic reagent or a metal. Examples of suitable organometallicreagents include alkyllithiums such as n-butyllithium, sec-butyllithiumor tert-butyllithium; aryllithiums such as phenyllithium or lithiumnaphtilide. Examples of suitable metal include magnesium. Preferredinert solvents include, for example, hydrocarbons such as hexane; etherssuch as diethyl ether, diisopropyl ether, DME, THF or 1,4-dioxane; ormixtures thereof. Reaction temperature is generally in the range of −100to 50° C., preferably in the range of from −100° C. to room temperature.Reaction time is, in general, from 1 minute to a day, preferably from 1hour to 10 hours.

A compound of formula (IIa) may be converted to a compound of formula(II) by any one of routes 1-4 below.

When R² is hydrogen, a compound of formula (II) may be prepared from acompound of formula (IIa) as illustrated by Route 1.

Step 3D: In this Step, a compound of formula (IIf) can be prepared byreduction of a compound of formula (IIa). The reduction of the carbonylgroup of compound (IIa) may be carried out by conventional procedures.In a typical procedure, the reduction is carried out by treatment withlithium aluminum hydride, lithium borohydride or boran in a suitableinert solvent. Suitable solvents include, for example, ethers such asTHF, DME or 1,4-dioxane. This reaction may be carried out at atemperature in the range from −20 to 100° C., usually from 20° C. to 65°C. for 30 minutes to 24 hours, usually 60 minutes to 10 hours. Analternative reduction procedure may be carried out by treatment with areduction agent such as BH₃Me₂S complex having(R)-3,3-diphenyl-1-methylpyrrolidino[1,2,C]-1,3,2-oxazaborole as aligand. Suitable inert solvents include THF. The reaction may be carriedout at a temperature of −10° C., for 30 minutes to 24 hours, usually 60minutes to 10 hours.

Step 3E-1: In this Step, a compound of formula (IIf) may be converted toa compound with a leaving group under conditions known to those skilledin the art. For example, the hydroxy group of the compound of formula(IIf) may be converted to the chloride using a chlorinating agent, e.g.thionyl chloride, oxalyl chloride in the presence or absence of an inertsolvent, e.g. halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride or 1,2-dichloroethane; ethers such asdiethyl ether, diisopropyl ether, THF or 1,4-dioxane; DMF or DMSO. Foranother example, the hydroxy group of the compound of formula (IIf) maybe converted to the sulfonate group using a sulfonating agent, e.g.para-toluenesulfonyl chloride, para-toluenesulfonic anhydride,methanesulfonyl chloride, methanesulfonic anhydride,trifluoromethanesulfonic anhydride in the presence of, or absence of abase, e.g. an alkali or alkaline earth metal hydroxide, alkoxide,carbonate, halide or hydride, such as sodium hydroxide, potassiumhydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide,sodium carbonate, potassium carbonate, potassium fluoride, sodiumhydride or potassium hydride, or an amine such as triethylamine,tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridinein the presence or absence of an inert solvent, e.g. aliphatichydrocarbons, such as hexane, heptane or petroleum ether; aromatichydrocarbons, such as benzene, toluene, o-dichlorobenzene, nitrobenzene,pyridine or xylene; halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride or 1,2-dichloroethane; ethers such asdiethyl ether, diisopropyl ether, THF or 1,4-dioxane; DMF or DMSO.

Step 3E-2: A compound of formula (IIe) may be prepared by azidointroduction. The compound obtained in the Step 3E-1 may be treated withdiphenylphosphoryl azide (DPPA), sodiumazide, or HN₃ in the presence ofa dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and aphosphine reagent such as triphenylphosphine. Preferably, this reactionmay be carried out in an inert solvent. Preferred inert solventsinclude, but are not limited to, THF, diethyl ether, DMF, benzene,toluene, xylene, o-dichlorobenzene, nitrobenzene, DCM,1,2-dichloroethane or DME; or mixtures thereof. The reduction may becarried out in the presence of a suitable reducing agent such as lithiumaluminum hydride, sodium borohydride, triethyl phosphite,triphenylphosphine, zinc, dibutyl tinhydride or diboran in an inertsolvent selected from, but not limited to, THF, diethyl ether, MeOH, andEtOH. If desired, the reaction may be carried out under acidicconditions in the presence of hydrochloric acid or acetic acid. Reactiontemperature is generally in the range of −100 to 250° C., preferably inthe range of 0° C. to the reflux temperature, but if necessary, lower orhigher temperature can be employed. Reaction time is, in general, from 1minute to a day, preferably from 20 minutes to 5 hours, however shorteror longer reaction times, if necessary, can be employed.

Step 3F: In this Step, a compound of formula (II) can be prepared byreduction of an azide compound of formula (IIe) with a reducing agent.This reaction may be carried out in the presence of a suitable reducingagent such as diboran, boran-methyl sulfide complex, or lithium aluminumhydride in an inert solvent such as THF or diethyl ether. The reactionmay also be carried out in similar conditions to those described in Step2D above. Reaction temperature is generally in the range of −100 to 250°C., preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timeis, in general, from 1 minute to a day, preferably from 20 minutes to 5hours, however shorter or longer reaction times, if necessary, can beemployed. The reduction may also be carried out under knownhydrogenation conditions such as in the presence of a metal catalystsuch as Raney nickel catalysts in the presence or absence of hydrazine,palladium catalysts or platinum catalysts under hydrogen atmosphere.This reaction may be carried out in an inert solvent such as MeOH, EtOH,or THF, in the presence or absence of hydrogen chloride. If necessary,this reduction may be carried out under pressure in the range from about0.5 to 10 kg/cm², preferably in the range from 1 to 6 kg/cm². Reactiontemperature is generally in the range of −100° C. to 250° C., preferablyin the range of 0° C. to the reflux temperature, but if necessary, loweror higher temperature can be employed. Reaction time is, in general,from 1 minute to 2 days, preferably from 20 minutes to 24 hours.Alternatively, when R² is hydrogen, a compound of formula (II) may beprepared form a compound of formula (IIa) as illustrated by Route 2.

wherein R′ is t-butylsulfinyl, phenethyl, NH₂, benzyl or diphenylmethyl.

Step 3G: In this step, a compound of formula (IIh) can be prepared bycoupling reaction of a compound of formula (IIa) with an amine offormula R′NH₂ in the presence of a dehydrating reagent and/or HCl-MeOHand/or Lewis Acid. A preferred dehydrating reagent includes sodiumsulfate, magnesium sulfate, calcium sulfate or methylformate. Examplesof suitable solvents include THF; 1,4-dioxane; DMF; acetonitrile;alcohols such as MeOH or EtOH; halogenated hydrocarbons such as DCM,1,2-dichloroethane, chloroform or carbon tetrachloride; or acetic acid.Reaction temperature is generally in the range of 0 to 200° C.,preferably in the range of from 100° C. to 140° C. Reaction time is, ingeneral, from 1 minute to a day, preferably from 5 minutes to 1 hour. Ifnecessary, microwave conditions are applied to the reaction.

Step 3H: In this step, a compound of formula (IIg) can be prepared byreduction of a compound of formula ((IIh) with a reducing agent. Thisreaction may be carried out in the presence of a suitable reducing agentsuch as diboran, boran-methyl sulfide complex, sodium borohydride,lithium borohydride, sodium borohydride, or lithium aluminum hydride inan inert solvent selected from THF and diethyl ether. Reactiontemperature is generally in the range of −100 to 250° C., preferably inthe range of 0° C. to the reflux temperature, but if necessary, lower orhigher temperature can be employed. Reaction time is, in general, from 1minute to a day, preferably from 20 minutes to 5 hours, however shorteror longer reaction times, if necessary, can be employed. The reductionmay also be carried out under known hydrogenation conditions such as inthe presence of a metal catalyst such as Raney nickel catalysts in thepresence or absence of hydrazine, palladium catalysts or platinumcatalysts under hydrogen atmosphere. This reaction may be carried out inan inert solvent such as MeOH, EtOH, and THF in the presence or absenceof hydrogen chloride. If necessary, this reduction may be carried outunder pressure in the range from about 0.5 to 10 kg/cm², preferably inthe range from 1 to 6 kg/cm². Examples of suitable solvents are similarto those mentioned in Step 3G. Reaction temperature is generally in therange of −100° C. to 250° C., preferably in the range of 0° C. to thereflux temperature, but if necessary, lower or higher temperature can beemployed. Reaction time is, in general, from 1 minute to 2 days,preferably from 20 minutes to 24 hours.

Step 3I: In this Step, a compound of the formula (II) can be prepared bydeprotection and/or salt formation of a compound of formula (IIg) underacidic conditions in an inert solvent using a method of Journal ofAmerican Chemical Society, 1999, 121, 268-269 by D. Cogan et. al.Suitable acids include, for example, but not limited to hydrogenchloride, hydrogen bromide, trifluoromethane sulfonic acid, acetic acidor p-toluenesulfonic acid. The reaction may be also carried out underknown hydrogenation conditions such as in the presence of a metalcatalyst such as palladium-carbon catalyst or platinum catalysts underhydrogen atmosphere. This reaction may be carried out in an inertsolvent such as MeOH, EtOH, and THF in the presence or absence ofhydrogen chloride. If necessary, this reduction may be carried out underpressure in the range from about 0.5 to 10 kg/cm², preferably in therange from 1 to 6 kg/cm². Reaction temperature is generally in the rangeof −100° C. to 250° C., preferably in the range of 0° C. to the refluxtemperature, but if necessary, lower or higher temperature can beemployed. Reaction time is, in general, from 1 minute to 2 days,preferably from 20 minutes to 24 hours.

wherein M is a metal, such as lithium; or a metal halide, such as MgZwherein Z is halogen.

In this route, a compound of the formula (II) can be prepared by themethods described in Step 3C, Step 3E-1 and E-2, and Step 3F above.

wherein R′ is t-butylsulfinyl, phenethyl, NH₂, benzyl or diphenylmethyl;and

R¹M is a suitable alkylating agent including an alkyl metal, such asalkyl lithium; or a Grignard reagent, R¹MZ, wherein Z is halogen; or

when R¹ is trifluoromethyl, then R¹M may betrifluoromethyltrimethylsilane (TMSCF₃) in the presence of a catalyticfluoride source, such as CsF or tetralkylammonium fluoride.

In this route, a compound of the formula (II) can be prepared by themethods described in Step 3G, Step 3C and Step 3I above.

Scheme 3′:

When R⁵ is (C₁-C₆)alkoxy, R⁶ is hydroxy, R⁷ is hydrogen, R² is hydrogenand R¹ is methyl, a compound of formula (II) may be converted to afurther compound of formula (II) by halogenation, according to theprocess illustrated below.

wherein X is halogen; R′ is (C₁-C₆)alkyl; and * indicates the (R)configuration.

Step-3′A

In this Step, ¥ compound of the formula (VII) can be prepared byO-acetylation of a compound of formula (II) under various conditions inan inert solvent using a method of Protective Groups in OrganicSynthesis (JOHN WILEY & SONS, Inc.); T. W. Greene and P. G. M. Wuts.Examples of suitable acetylating agents include acetic anhydride andacetyl chloride. This reaction may be carried out in an inert solventsuch as ethers such as tetrahydrofuran, diethyl ether,1,2-dimethoxyethane or 1,4-dioxane; halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride;or pyridine under the presence or absence of base. Examples of suitablebases include trialkylamines such as triethylamine,diisopropylethylamine; pyridine and 4-dimethylaminopyridine. Reactiontemperature is generally in the range of −20° C. to 150° C., preferablyin the range of 0° C. to 100° C., but if necessary, lower or highertemperature can be employed. Reaction time is, in general, from 1 minuteto 2 days, preferably from 20 minutes to 24 hours.

Step-3′B

In this Step, a compound of the formula (VIII) can be prepared byhalogenation (electrophilic aromatic substitution reaction) of acompound of formula (VII) under various known conditions in an inertsolvent. Preferred halogenation agents are selected from, for example,but not limited to: bromine, chlorine, iodide, N-halosuccinimide such asN-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide. Examplesof suitable inert aqueous or non-aqueous organic solvents include:ethers, such as diethylether, tetrahydrofuran or 1,4-dioxane;halogenated hydrocarbons, such as dichloromethane, dichloroethane orchloroform; N,N-dialkylformamide such as

N,N-dimethylformamide and acid solution such as acetic acid andtrifluoroacetic acid; or mixtures thereof. The reaction can be carriedout at a temperature in the range of from 20° C. to 150° C., preferablyin the range of from 20° C. to 100° C. Reaction times are, in general,from 10 minutes to 4 days, preferably from 30 minutes to 24 hours.

Step-3′C

In this Step, a compound of the formula (II) can be prepared bydeprotection and/or salt formation of a compound of formula (VIII) underacidic conditions in an inert solvent using a method of ProtectiveGroups in Organic Synthesis (JOHN WILEY & SONS, Inc.); T. W. Greene andP. G. M. Wuts. Suitable acids include, for example, but not limited tohydrogen chloride, hydrogen bromide, triflupromethane sulfonic acid,acetic acid or p-toluenesulfonic acid. The reaction can be carried outat a temperature in the range of from 20° C. to 150° C., preferably inthe range of from 20° C. to 100° C. Reaction times are, in general, from10 minutes to 4 days, preferably from 30 minutes to 24 hours.

Scheme 4:

When R⁵ is methyl, R⁶ is methoxy, R⁷ is halogen, R² is hydrogen and R¹is methyl, a compound of formula (II) may be prepared by the processillustrated below.

wherein R′ is alkyl; and X is halogen, preferably chlorine.

Step 4A:

In this Step, a compound of formulae (XI) and (XII) can be prepared bydehydration and reduction of a compound of formula (X) and a suitable(R)-alkylsulfinylamide in the presence of a catalyst and reducing agentin an inert solvent. Dehydration is conducted in the presence of adehydrating agent. Examples of suitable dehydrating agents include:hydrogen halides such as hydrogen chloride and hydrogen bromide;sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid;sulfonyichlorides such as methansulfonylchloride andp-toluenesulfonylchloride; methoxycarbonylsulfamoyltriethylammoniumhydroxide; p-toluenesulfonylisocyanate; and titanium(IV) ethoxide.Reaction temperatures are generally in the range of from 0 to 200° C.,preferably in the range of from 50° C. to 100° C. Reaction times are, ingeneral, from 1 minute to 48 hours, preferably from 12 hours to 24hours. The reduction may be carried out in the presence of a suitablereducing agent in an inert solvent or without solvent. A preferredreducing agent is selected from, for example, but not limited to, sodiumborohydride, lithium aluminium hydride, lithium borohydride, Fe, Sn orZn. A preferred (R)-alkylsulfinylamide is(R)-(+)-2-methyl-2-propanesulfinylamide. Reaction temperatures aregenerally in the range of from −78° C. to room temperature, preferablyin the range of from −70° C. to 0° C. Reaction times are, in general,from 1 minute to a day, preferably from 3 hours to 6 hours. Examples ofsuitable solvents include: tetrahydrofuran; 1,4-dioxane;N,N-dimethylformamide; acetonitrile; alcohols, such as methanol orethanol; halogenated hydrocarbons, such asdichloromethane,1,2-dichloroethane, chloroform or carbon tetrachloride;and acetic acid.

Step 4B:

In this Step, a compound of the formula (II) can be prepared bydeprotection and/or salt formation of a compound of formula (XI) or(XII) under acidic conditions in an inert solvent using a method ofJournal of American Chemical Society, 1999, 121, 268-269 by D. Cogan et.al. Suitable acids include, for example, but not limited to hydrogenchloride, hydrogen bromide, trifluoromethane sulfonic acid, acetic acidor p-toluenesulfonic acid. The reaction may be also carried out underknown hydrogenation conditions such as in the presence of a metalcatalyst such as palladium-carbon catalysts or platinum catalysts underhydrogen atmosphere. This reaction may be carried out in an inertsolvent such as methanol, ethanol, and THF in the presence or absence ofhydrogen chloride. If necessary, this reduction may be carried out underpressure in the range from about 0.5 to 10 kg/cm², preferably in therange from 1 to 6 kg/cm². Reaction temperature is generally in the rangeof −100° C. to 250° C., preferably in the range of 0° C. to the refluxtemperature, but if necessary, lower or higher temperature can beemployed. Reaction time is, in general, from 1 minute to 2 days,preferably from 20 minutes to 24 hours.

Scheme 5:

When R⁵ is (C₁-C₆)alkyl, R⁶ is hydroxy, R⁷ is fluorine or chlorine, andR¹ and R² are both hydrogen, a compound of formula (II) may be preparedby the process illustrated below.

wherein X is fluorine or chlorine; and R' is alkyl.

Step 5A: A compound of formula (XVI) can be prepared by formylationreaction (electrophilic aromatic substitution reaction) from a compoundof formula (XV) with formyl cation equivalents in a solvent. Examples offormyl cation equivalents include a combination of dichloromethylalkylether such as dichloromethylmethylether and dichloromethyl(n-butyl)etherwith lewis acids such as tin tetrachloride, titanium tetrachloride andaluminium trichloride (Rieche method) and a combination of phosphorousoxychloride, thionyl chloride, oxalyl chloride andtrifluoromethanesulfonic anhydride as activating reagents withN,N-dialkylformamides such as N,N-dimethylformamide, N-methylformamideand N-methylformanilide as reactants (Vilsmeier method); and acombination of hexamethylenetetramine (HMTA) with trifluoroacetic acid(Duff method). There is likewise no particular restriction on the natureof the catalysts used, and any catalysts commonly used in reactions ofthis type can equally be used here. This reaction can be carried out inthe presence or absence of an inert solvent. Suitable solvents include,for example, ethers such as tetrahydrofuran,1,2-dimethoxyethane or1,4-dioxane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform or carbon tetrachloride; orN,N-dialkylformamides, acetonitrile, and trifluoroacetic acid. Thereaction can be carried out at a temperature of from −78° C. to 200° C.,more preferably from −20° C. to 100° C. Reaction time is, in general,from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours, willusually suffice.

Step 5B: In this step, a compound of formula (XVII) can be prepared byreduction of a compound of formula (XVI) and a suitable(R/S)-alkylsulfinylamide such as disclosed in step 4A.

Step 5C:

In this step, a compound of the formula (II) can be prepared from acompound of formula (XVII) by the method described in Step 4B above.

Scheme 6:

When R⁵ is (C₁-C₆)alkyl, R⁶ is methoxy, R⁷ is halogen, and R¹ and R² areboth hydrogen, a compound of formula (II) may be prepared by the processillustrated below.

wherein X is halogen.

Step 6A:

In this Step, the compound of the formula (XX) can be prepared byimidomethylation (electrophilic aromatic substitution reaction) of thecompound of formula (XIX) with O-phthalimidomethyl trichloroacetimidateand a catalytic amount of trimethylsilyl triflate (TMSOTf) [Tetrahedron60 (2004) 4773-4780] in an inert solvent. Examples of suitable inertorganic solvents include: ethers, such as diethylether, tetrahydrofuranor 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane,dichloroethane or chloroform; N,N-dialkylformamide such asN,N-dimethylformamide; or mixtures thereof. The reaction can be carriedout at a temperature in the range of from 20° C. to 150° C., preferablyin the range of from 20° C. to 100° C. Reaction times are, in general,from 10 minutes to 4 days, preferably from 30 minutes to 24 hours.

Step 6B:

In this Step, a compound of the formula (II) can be prepared bydeprotection of a compound of formula (XX) under various conditions inan inert solvent using a method of Protective Groups in OrganicSynthesis (JOHN WILEY & SONS, Inc.); T. W. Greene and P. G. M. Wuts.Examples of suitable deprotecting agents are selected from, for example,but not limited to, hydrazine, phenylhydrazine and sodium sulfide. Thisreaction may be carried out in an inert solvent such as ethers such astetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or 1,4-dioxane,alcohols such as methanol, ethanol, 2-propanol ; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform orcarbon tetrachloride; and acidic solutions such as hydrochloricsolution, acetic acid. Reaction temperature is generally in the range of20° C. to 150° C., preferably in the range of 20° C. to 100° C., but ifnecessary, lower or higher temperature can be employed. Reaction timeis, in general, from 1 minute to 2 days, preferably from 20 minutes to24 hours.

Scheme 7:

When R⁵ and R⁷ are both hydrogen, R⁶ is hydroxymethyl, R¹ is methyl andR² is hydrogen, a compound of formula (II) may be prepared by theprocess illustrated below.

Step 7A: In this Step, the compound of formula (XXIII) may be preparedby carbon monoxide insertion reaction from the compound of formula(XXII) with carbon monoxide and alcohol (e.g. MeOH, EtOH) in thepresence of a catalyst and/or base in an inert solvent. Examples ofsuitable catalysts include: palladium reagents, such as palladiumacetate or palladium dibenzylacetone. Examples of suitable bases includeN,N-diisopropylethylamine, N-methylmorpholine or triethylamine. Ifdesired, this reaction may be carried out in the presence or absence ofan additive such as 1,1′-bis(diphenylphosphino)ferrocene,triphenylphosphine or 1,3-bis-(diphenylphosphino)propane (DPPP). Thereaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include acetone;nitromethane; DMF; sulfolane; DMSO; NMP; 2-butanone; acetonitrile;halogenated hydrocarbons such as DCM, dichloroethane or chloroform; orethers, such as THF or 1,4-dioxane. The reaction can take place over awide range of temperatures, and the precise reaction temperature is notcritical to the invention. The preferred reaction temperature willdepend upon such factors as the nature of the solvent, and the startingmaterial or reagent used. However, in general, we find it convenient tocarry out the reaction at a temperature of from −20° C. to 150° C., morepreferably from about 50° C. to 80° C. The time required for thereaction may also vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents and solventemployed. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of 30 minutes to 24 hours,more preferably 1 hour to 10 hours, will usually suffice.

Step 7B:

In this Step, the compound of formula (XXIV) can be prepared byreduction of the compound of formula (XXIII) in the presence of areducing agent and a catalyst in an inert solvent. A preferred reducingagent is selected from, for example, but not limited to, sodiumborohydride, lithium aluminium hydride, lithium borohydride,diisobutylaluminium hydride (DIBAL-H), Fe, Sn or Zn. Reactiontemperatures are generally in the range of from −78° C. to 150° C.,preferably in the range of from −70° C. to 100° C. Reaction times are,in general, from 1 minute to a day, preferably from 3 hours to 6 hours.Examples of suitable solvents include: ethers such as tetrahydrofuran,diethyl ether, 1,2-dimethoxyethane or 1,4-dioxane; alcohols such asmethanol, ethanol, 2-propanol; halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride;hydrocarbons, such as hexane, benzene, and toluene.

Step 7C

In this Step, the compound of formula (II) can be prepared from thecompound of formula (XXIV) by deprotection and/or salt formation undervarious conditions in an inert solvent using a method of ProtectiveGroups in Organic Synthesis (JOHN WILEY & SONS, Inc.); T. W. Greene andP. G. M. Wuts. Preferred acid conditions include, for example, but notlimited to hydrogen chloride, hydrogen bromide, trifluoromethanesulfonicacid, trifluoroacetic acid, acetic acid or p-toluenesulfonic acid.Reaction temperature is generally in the range of −20° C. to 150° C.,preferably in the range of 0° C. to the reflux temperature, but ifnecessary, lower or higher temperature can be employed. Reaction timeis, in general, from 1 minute to 2 days, preferably from 20 minutes to24 hours.

Scheme 8:

When R⁵ is (C₁-C₆)alkyl, R⁶ is hydroxymethytl, R⁷ is fluorine orchlorine, R¹ is methyl and R² is hydrogen, a compound of formula (II)may be prepared by the process illustrated below.

wherein X¹ is bromine or iodine; and X² is fluorine or chlorine.

Step 8A:

In this step, a compound of formula (XXVII) can be prepared by reductiveamination reaction of a sulfonamide with a ketone of formula (XXVI) bythe method described in Step 4A above.

Step 8B:

In this step, a compound of formula (XXVIII) can be prepared by carbonmonoxide insertion reaction of a compound of formula (XXVII) by themethod described in Step 7A above.

Step 8C:

In this step, a compound of formula (XXIX) can be prepared by reductionreaction of a compound of formula (XXVIII) by the method described inStep 7B above.

Step 8D:

In this step, a compound of the formula (II) can be prepared from acompound of formula (XXIX) by the method described in Step 4B above.

Schemes 9 to 15 provide examples of processes useful for the preparationof compounds of formula (III).

Scheme 9:

When R⁴ is a 1,1-dimethylalkyl group, a compound of formula (III) may beprepared by the process illustrated below:

wherein L is a suitable leaving group; R is (C₁-C₃)alkyl, optionallysubstituted with halogen, hydroxy, or (C₁-C₃)alkoxy; and R′ is(C₁-C₆)alkyl.

Step 9A: In this Step, an amide compound of formula (XXXII) can beprepared from a compound of formula (XXXI) by the same procedure as Step1A.

Step 9B:

In this Step, a compound of formula (XXXIII) can be prepared by reactionof a compound of formula (XXXII) with an organometallic reagent R-M,wherein M is a metal such as lithium, or MgZ wherein Z is a halogen. R-Mcan be prepared from a halide compound of R. For example, R-M, in whichM represents MgZ, can be generated by stirring Mg, R⁻Z, dibromoethaneand I₂ at a temperature in the range of between 30-80° C. This reactionmay be carried out in the presence of an organometallic reagent or ametal. Examples of suitable organometallic reagents includealkyllithiums such as n-butyllithium, sec-butyllithium ortert-butyllithium; aryllithiums such as phenyllithium or lithiumnaphtilide. Examples of suitable metals include magnesium. Preferredinert solvents include, for example, hydrocarbons such as hexane; etherssuch as diethyl ether, diisopropyl ether, DME, THF or 1,4-dioxane; ormixtures thereof. Reaction temperature is generally in the range of −100to 50° C., preferably in the range of from −100° C. to room temperature.Reaction time is, in general, from 1 minute to a day, preferably from 1hour to 10 hours.

Step 9C: In this Step, a compound of formula (XXXIV) can be prepared byan alkylation reaction of a compound of formula (XXXIII) with ageminal-alkylating reagent in an inert solvent. Examples of preferredalkylating agents include trialkylmetals such as trimethylaluminum,triethylaluminum; alkylmagnesium halides such as methylmagnesium bromidein the presence of an additive compound such as lithium bromide;dialkyltitanium halides such as dimethyltitanium dichloride prepared bydimethylzinc and titanium chloride. Most preferably, the alkylatingagent is dimethyltitanium dichloride. Examples of preferred inertsolvents for the reaction include halogenated hydrocarbons, such as DCM,1,2-dichloroethane, chloroform or carbon tetrachloride; ethers, such asdiethyl ether, diisopropyl ether, DME, THF and 1,4-dioxane;hydrocarbons, such as n-hexane, cyclohexane, benzene and toluene; ormixtures thereof. Reaction temperatures are generally in the range offrom −100 to 200° C., preferably in the range of from −40° C. to 100° C.Reaction times are, in general, from 1 minute to a day, preferably from1 hour to 10 hours.

Step 9D: In this Step, a compound of formula (XXXV) can be prepared froma compound of formula (XXXIV) by the same procedure as described in Step3A.

Step 9E: In this Step, an acid compound of formula (III) may be preparedby hydrolysis of a compound of formula (XXXV) in a solvent. Thehydrolysis may be carried out by conventional procedures. In a typicalprocedure, the hydrolysis is carried out under basic conditions in thepresence of water. Suitable bases include, for example, sodiumhydroxide, potassium hydroxide or lithium hydroxide. Suitable solventsinclude, for example, alcohols such as MeOH, EtOH, propanol, butanol,2-methoxyethanol or ethylene gylcol; ethers such as THF, DME or1,4-dioxane; amides such as DMF or hexamethylphosphorictriamide; orsulfoxides such as DMSO. This reaction may be carried out at atemperature in the range from −20 to 100° C., usually from 20° C. to 65°C. for 30 minutes to 24 hours, usually 60 minutes to 10 hours. Thehydrolysis may also be carried out under acid conditions, e.g. in thepresence of hydrogen halides such as hydrogen chloride and hydrogenbromide; sulfonic acids such as p-toluenesulfonic acid andbenzenesulfonic acid; pyridium p-toluenesulfonate; and carboxylic acidssuch as acetic acid and trifluoroacetic acid. Suitable solvents include,for example, alcohols such as MeOH, EtOH, propanol, butanol,2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME and1,4-dioxane; amides such as DMF and hexamethylphosphorictriamide; andsulfoxides such as DMSO. This reaction may be carried out at atemperature in the range from −20 to 100° C., usually from 20° C. to 65°C. for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Scheme 10:

When Y² is N and Y¹ and Y² are both CH, a compound of formula (III) maybe prepared by the process illustrated below.

wherein R is (C₁-C₆)alkyl; and X is halogen, preferably chlorine.

Step 10A: In this Step, a compound of formula (XXXVII) can be preparedby N-substituted acrylation of a compound of formula (XXXVI) withdialkyl alkoxy methylenemalonate in a reaction inert solvent or withoutsolvent. Examples of suitable solvents include alcohols such as MeOH,EtOH, propanol, butanol, 2-methoxyethanol, and ethylene glycol; etherssuch as THF, DME, and 1,4-dioxane. The reaction can be carried out at atemperature in the range from 50° C. to 150° C. for 30 minutes to 24hours, usually 60 minutes to 3 hours.

Step 10B: In this Step, a compound of formula (XXXVIII) can be preparedby thermal cyclization of a compound of formula (XXXVII) in a reactioninert solvent. Examples of suitable solvents include ethers such asphenyl ether. This reaction can be carried out at a temperature in therange from 200 to 300° C. for 30 minutes to 24 hours, usually 250° C.for 30 minutes to 5 hours. (Journal of Medicinal chemistry, 1998, Vol41, No 25.)

Step 10C: In this Step, a compound of formula (XXXIX) can be prepared byhalogenation of a compound of formula (XXXVIII). The reaction is carriedout under halogenation conditions with a halogenating reagent in areaction inert solvent or without solvent. Examples of suitable solventsinclude THF, 1,4-dioxane, DMF, acetonitrile; halogenated hydrocarbons,such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride andacetic acid. Examples of suitable halogenating reagents includephosphorus oxyhalide such as phosphorus oxychloride and phosphorusoxybromide. The reaction can be carried out at a temperature of from 0°C. to 200° C., more preferably from ambient temperature to 150° C.Reaction times are, in general, from 5 minutes to 48 hours, morepreferably 30 minutes to 6 hours, will usually suffice.

Step 10D: In this Step, a dehalogenated compound of formula (XL) can beprepared by hydrogenation of a compound of formula (XXXIX) in a solvent.Hydrogenation reaction is carried out under, for example, knownhydrogenolysis conditions in the presence of a metal catalyst underhydrogen atmosphere or in the presence of hydrogen sources such asformic acid or ammonium formate in a reaction inert solvent. If desired,the reaction is carried out under basic conditions, for example, in thepresence of triethylamine. Preferred reagents are selected from, forexample, nickel catalysts such as Raney nickel, palladium-carbon,palladiumhydroxide-carbon, platinumoxide, platinum-carbon,ruthenium-carbon, rhodium-aluminumoxide,tris[triphenyphosphine]rhodiumchloride. Examples of suitable reactioninert aqueous or non-aqueous organic solvents include alcohols, such asMeOH, EtOH; ethers, such as THF or 1,4-dioxane; acetone;dimethylformamide; halogenated hydrocarbons, such as DCM, dichloroethaneor chloroform; and acetic acid or mixtures thereof. The reaction can becarried out at a temperature in the range from of 20° C. to 100° C.,preferably in the range of 20° C. to 60° C. Reaction times are, ingeneral, from 10 minutes to 48 hours, preferably 30 minutes to 24 hours.This reaction can be carried out under hydrogen atmosphere at a pressureranging from 1 to 100 atom, preferably from 1 to 10 atm. Preferredconditions comprise the use of 5 or 10% palladium-carbon at ambienttemperature for 1 to 24 hours under hydrogen atmosphere using a balloon.

Step 10E: In this Step, an acid compound of formula (III) can beprepared by hydrolysis of the compound of formula (XL) in a solvent bythe method as described in Step 9E.

Scheme 11:

When Y¹ is N, Y² is CH and Y³ is CH, a compound of formula (III) may beprepared by the process illustrated below.

Step 11A: In this Step, a N-oxide compound of formula (XLII) can beprepared by oxidation of a compound of formula (XLI) in a reaction inertsolvent. The oxidation reaction may be carried out in the absence orpresence of an additive agent in a reaction inert solvent. Examples ofpreferred oxidation reagents are meta-chloroperbenzoic acid (mCPBA),hydrogen peroxide, peracetic acid. Examples of preferred reaction inertsolvents include halogenated hydrocarbons, such as methylene chloride,chloroform, carbon tetrachloride and dichloroethane; ethers, such asdiethyl ether, diisopropyl ether, DME, THF and 1,4-dioxane;acetonitrile, acetic acid and water or mixtures thereof. Reactiontemperatures are generally in the range of 0° C. to 250° C., morepreferably in the range of 0° C. to 100° C. Reaction times are, ingeneral, from 1 minute to a 10 day, more preferably from 20 minutes to 6hours. This reaction may be carried out in the presence of a suitablecatalyst. There is likewise no particular restriction on the nature ofthe catalyst used, and any catalyst commonly used in reactions of thistype may equally be used here. Examples of such catalysts includemethyltrioxorhenium(VII), tungstic acid and sodium tungstate dehydrate.

Step 11B: In this Step, a cyano compound of formula (XLIII) can beprepared by cyanation of a compound of formula (XLII) in a reactioninert solvent. Examples of preferred cyanation reagents includetrimethylsilanecarbonitrile (TMSCN), the combination oftrimethylchlorosilane and sodium cyanide, and the combination ofacylating agents such as N,N-dimethylcarbamoyl chloride withtrimethylsilanecarbonitrile (TMSCN). A preferred cyanation reagent istrimethylsilanecarbonitrile (TMSCN) in the presence of a base suchtriethylamine in a reaction inert solvent. Examples of preferredreaction inert solvents include halogenated hydrocarbons, such as.methylene chloride, chloroform, carbon tetrachloride and dichloroethane;ethers, such as diethyl ether, DME, THF and 1,4-dioxane; acetonitrile,DMF, DMSO or mixtures thereof. Reaction temperatures are generally inthe range of 0° C. to 250° C., more preferably in the range of 0° C. to100° C. Reaction times are, in general, from 1 minute to 10 days, morepreferably from 20 minutes to 24 hours.

Step 11C: In this Step, an acid compound of formula (III) can beprepared by hydrolysis of a cyano compound of formula (XLIII) in asolvent. The hydrolysis can be carried out by conventional procedures.In a typical procedure, the hydrolysis may be carried out under basicconditions, e.g. in the presence of sodium hydroxide, potassiumhydroxide or lithium hydroxide. Examples of suitable solvents includealcohols such as MeOH, EtOH, propanol, butanol, 2-methoxyethanol, andethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides suchas DMF and hexamethylphosphorictriamide; and sulfoxides such as DMSO.Preferable solvents are MeOH, EtOH, propanol, THF, DME, 1,4-dioxane, DMFand DMSO. This reaction can be carried out at a temperature in the rangefrom −20 to 150° C., usually from 20° C. to 100° C. for 30 minutes to 24hours, usually 60 minutes to 10 hours.

Scheme 12:

When wherein Y³ is N, Y¹ and Y² are CH, and R⁴ is trifluoromethyl, acompound of formula (III) may be prepared by the process illustratedbelow.

wherein R is (C₁-C₆)alkyl.

Step 12A: In this Step, a N-oxide compound of formula (XLV) can beprepared by oxidation of a compound of formula (XLIV) in a solvent bythe method as described in Step 11A.

Step 12B: In this Step, a compound of formula (XLVI) can be prepared bytrifluoromethylation of a compound of formula (XLV) in a reaction inertsolvent. Examples of preferred trifluoromethylation reagents include thecombination of trifluoromethyltrimethylsilane (TMSCF₃) and initiatorreagents. Examples of preferred catalytic initiator reagents includetetrabutylammonium fluoride cesium fluoride, lithium acetate, sodiumacetate, potassium acetate, tetrabutylammonium acetate, lithiumpivalate, lithium benzoate, potassium t-butoxide, sodium t-butoxide.Examples of preferred reaction inert solvents include hydrocarbons, suchas hexane, benzene, toluene; halogenated hydrocarbons, such as methylenechloride, chloroform, carbon tetrachloride and dichloroethane; ethers,such as diethyl ether, diisopropyl ether, DME, THF and 1,4-dioxane;acetonitrile, EtOAc, DMF, DMSO or mixtures thereof. Reactiontemperatures are generally in the range of −78° C. to 200° C., morepreferably in the range of −78° C. to 100° C. Reaction times are, ingeneral, from 1 minute to 10 days, more preferably from 20 minutes to 24hours.

Step 12C: In this Step, an acid compound of formula (III) can beprepared by hydrolysis ofa compound of formula (XLVI) in a solvent bythe method as described in Step 9E.

Scheme 13:

When Y³ is N and Y¹ and Y² are CH, a compound of formula (III) may beprepared by the process illustrated below.

wherein R″ is (C₁-C₆)alkyl or benzyl; and M is a metal, such as lithium,or MgX, wherein X is hydrogen or halogen.

Step 13A: In this Step, a 1,2-dihydroquinoline compound of formula(XLVIII) can be prepared by alkylation of a compound of formula (XLVII)in a reaction inert solvent. The organometallic compound of formula R⁴-Mcan be prepared by reaction of a halide compound of R⁴, wherein R⁴ isalkyl. M represents a metal such as lithium, or MgX, wherein Xrepresents a hydrogen atom, a halogen atom such as, fluorine, chlorine,bromine or iodine. Examples of suitable organometallic reagents includealkyllithiums such as methyllithium, n-butyllithium, sec-butyllithiumand tert-butyllithium; aryllithiums such as phenyllithium and lithiumnaphtilide; alkylmagnesium halide such as methylmagnesium halide,isopropylmagnesium halide, and t-butylmagnesium halide; arylmagnesiumhalide such as phenylmagnesium halide. Examples of preferred reactioninert solvents include hydrocarbons, such as hexane; ethers, such asdiethyl ether, diisopropyl ether, DME, THF and 1,4-dioxane; or mixturesthereof. Reaction temperatures are generally in the range of −100 to100° C., preferably in the range of from −100° C. to room temperature.Reaction times are, in general, from 1 minute to a day, preferably from1 hour to 24 hours.

Step 13B: In this Step, a compound of formula (XLIX) can be prepared byoxidation of a compound of formula (XLVIII) in a solvent. Examples ofsuitable oxidative agents include Cr-reagents, such as chromium trioxide(CrO₃), potassium chromate (K₂CrO₄), potassium dichromate (K₂Cr₂O₇);Mn-reagents, such as manganese dioxide (MnO₂), potassium permanganate(KMnO₄); quinine reagents, such as 2,3,5,6,-tetrachloro-1,4-benzoquinone(p-chloranil), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); and airoxidation. Examples of suitable solvents include THF, 1,4-dioxane,acetone, DMF, acetonitrile, halogenated hydrocarbons (e.g., DCM,dichloroethane, chloroform), water; or mixtures thereof. The reactioncan take place over a wide range of temperatures, and the precisereaction temperature is not critical to the invention. The preferredreaction temperature will depend upon such factors as the nature of thesolvent, and the starting material or reagent used. However, in general,we find it convenient to carry out the reaction at a temperature of from−78° C. to 100° C., more preferably from about −60° C. to 60° C. Thetime required for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the reagentsand solvent employed. However, provided that the reaction is effectedunder the preferred conditions outlined above, a period of 1 minute to24 hours, more preferably 30 minutes to 12 hours, will usually suffice.

Step 13C: In this Step, an acid compound of formula (III) can beprepared by hydrolysis of a compound of formula (XLIX) in a solvent bythe method as described in Step 9E.

Scheme 14

When R⁴ is 1-methyl-1-trifluoromethylalkyl, a compound of formula (III)may be prepared by the process illustrated below.

wherein R is (C₁-C₃)alkyl; and X is halogen, O-mesylate, O-tosylate orO-triflate; and R′ is (C₁-C₆)alkyl.

Step 14A

In this Step, a compound of formula (LI) can be prepared by nucleophilictrifluoromethylation of a compound of formula (L) in a reaction inertsolvent. Examples of preferred trifluoromethylation reagents include thecombination of trifluoromethyltrimethylsilane (TMSCF₃) and initiatorreagents. Examples of preferred catalytic initiator reagents includetetrabutylammonium fluoride (TBAF), cesium fluoride (CsF), lithiumacetate (AcOLi), sodium acetate (AcONa), potassium acetate (AcOK),tetrabutylammonium acetate (AcO-nNBu4), lithium pivalate (t-BuCO2Li),lithium benzoate (PhCO2Li), potassium t-butoxide (KO-tBu), and sodiumt-butoxide (NaO-tBu). Examples of preferred reaction inert solventsinclude hydrocarbons, such as hexane, benzene, toluene; halogenatedhydrocarbons, such as methylene chloride, chloroform, carbontetrachloride and dichloroethane; ethers; such as diethyl ether,diisopropyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran anddioxane; acetonitrile; ethyl acetate; N,N-dimethylformamide (DMF);dimethylsulfoxide (DMSO); or mixtures thereof. Reaction temperatures aregenerally in the range of −78° C. to 200° C., more preferably in therange of −78° C. to 100° C. Reaction times are, in general, from 1minute to 10 days, more preferably from 10 minutes to 24 hours.

Step 14B

In this Step, a compound of the formula (LII) can be prepared bydeprotection of a compound of formula (LI) under various conditions inan inert solvent using a method of Protective Groups in OrganicSynthesis (JOHN WILEY & SONS, Inc.); T. W. Greene and P. G. M. Wuts.Examples of suitable deprotecting agents are selected from, for example,but not limited to, acid conditions using hydrochloric acid, citricacid, hydrogen fluoride (HF) or polystyrene sulfonic acid, tetraammoniumfluoride such as tetrabutylammonium fluoride and basic conditions usingpotassium carbonate. This reaction may be carried out in an inertsolvent such as ethers such as tetrahydrofuran, diethyl ether,1,2-dimethoxyethane or 1,4-dioxane; halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride;acetonitrile; dimethylsulfoxide;

N,N-dimethylformamide; hydrocarbons, such as n-hexane, cyclohexane,benzene and toluene; or mixtures thereof. Reaction temperature isgenerally in the range of 20° C. to 150° C., preferably in the range of20° C. to 100° C., but if necessary, lower or higher temperature can beemployed. Reaction time is, in general, from 1 minute to 2 days,preferably from 20 minutes to 24 hours.

Step 14C

In this Step, a compound of formula (LIII) can be prepared byhalogenation, O-mesylation, O-tosylation and O-triflate of a compound offormula (LII) in a reaction inert solvent or without solvent.

The halogenation reaction can be carried out using a halogenatingreagent in an inert solvent or without solvent. Examples of suitablesolvents include tetrahydrofuran; 1,4-dioxane; N,N-dimethylformamide;acetonitrile; halogenated hydrocarbons, such as dichloromethane,1,2-dichloroethane, chloroform or carbon tetrachloride; and acetic acid.Example of suitable halogenating reagents include thionyl chloride,oxalyl chloride, phosphorus pentachloride, phosphorus tribromide,phosphorus oxyhalide such as phosphorus oxychloride and phosphorusoxybromide, and lewis acids such as titanium chloride, tin chloride andaluminium chloride. The reaction can be carried out at a temperature offrom −78° C. to 200° C., more preferably from −20° C. to 150° C.Reaction times are, in general, from 5 minute to 10 days, morepreferably from 30 minutes to 24 hours.

The O-mesylation, O-tosylation and O-triflate reactions can be carriedout by the reaction of O-activating reagents with a compound of formula(LII) in the presence of a base in an inert solvent or without solvent.Examples of suitable O-activation reagents include methanesulfonylchloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chlorideand trifluoromethanesulfonic acid anhydride. Examples of suitable baseinclude alkyl lithium such as n-butyl lithium, sec-butyl lithium andtert-butyl lithium; potassium t-butoxide and sodium t-butoxide(NaO-tBu); triethylamine, diisopropylethylamine, 4-dimethylaminopyridineand pyridine. Examples of preferred reaction inert solvents includehydrocarbons, such as hexane, benzene, toluene; halogenatedhydrocarbons, such as methylene chloride, chloroform, carbontetrachloride and dichloroethane; ethers; such as diethyl ether,diisopropyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran anddioxane; acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide(DMSO) or mixtures thereof. The reaction can be carried out at atemperature of from −78° C. to 150° C., more preferably from −78° C. to100° C. Reaction times are, in general, from 5 minute to 48 days, morepreferably from 30 minutes to 24 hours.

Step 14D

In this Step, a compound of formula (LIV) can be prepared by reaction ofa compound of formula (LIII) with an alkylating reagent in an inertsolvent. Examples of preferred alkylating agents include trialkylmetalssuch as trimethylaluminum, triethylaluminum; and alkylmagnesium halidessuch as methylmagnesium bromide in the presence of additive compoundsuch as lithium bromide; or dialkyltitanium halides such asdimethyltitanium dichloride prepared by dimethylzinc and titaniumchloride; and is most preferably trimethylaluminum. Examples ofpreferred inert solvents for the reaction include halogenatedhydrocarbons, such as dichloromethane (DCM), 1,2-dichloroethane,chloroform or carbon tetrachloride; ethers, such as diethyl ether,diisopropyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF) and1,4-dioxane; hydrocarbons, such as n-hexane, cyclohexane, benzene andtoluene; or mixtures thereof. Reaction temperatures are generally in therange of from −100° C. to 200° C., preferably in the range of from −40°C. to 100° C. Reaction times are, in general, from 1 minute to 10 days,preferably from 1 hour to 24 hours.

Step 14E

In this Step, a compound of formula (LV) can be prepared byalkoxycarbonyl insertion reaction of a compound of formula (LIV) in asolvent by the method as described in Step 9D.

Step 14F

In this Step, an acid compound of formula (III) can be prepared byhydrolysis of a compound of formula (LV) in a solvent by the method asdescribed in Step 9E.

The various general methods described above may be useful for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not affect groups in the molecule which are desired in the finalproduct. The starting materials are commercially available or can beeasily prepared by the man skilled in the art by routine experiment.

Method for Assessing Biological Activities Human VR1 Antagonist Assay

VR1 antagonistic activity can be determined by the Ca²⁺ imaging assayusing human VR1 highly expressing cells. The cells that highly expresshuman VR1 receptors are obtainable from several different conventionalmethods. The one standard method is cloning from human Dorsal RootGanglion (DRG) or kidney according to the methods such as described inthe journal article; Nature, 389, pp 816-824, 1997. Alternatively VR1receptors highly expressing human keratinocytes are also known andpublished in the journal article (Biochemical and Biophysical ResearchCommunications, 291, pp 124-129, 2002). In this article, humankeratinocytes demonstrated VR1 mediated intracellular Ca²⁺ increase byaddition of capsaicin. Furthermore, the method to up regulate human VR1gene, which is usually a silent gene or don't produce detectable levelof VR1 receptors, is also available to obtain propriety cells. Suchgenetic modification method was described in detail; Nat. Biotechnol.,19, pp 440-445, 2001.

The cells that express human VR1 receptors were maintained in cultureflask at 37° C. in an environment containing 5% CO₂ until use in theassay. The intracellular Ca²⁺ imaging assay to determine VR1antagonistic activities were done by following procedures. The culturemedium was removed from the flask and fura-2/AM fluorescent calciumindicator was added to the flask at a concentration of 5 μM in themedium. The flask was placed in CO₂ incubator and incubated for 1 hour.Then the cells expressing the human VR1 receptors were detached from theflask follow by washing with phosphate buffer saline, PBS(−) andre-suspended in assay buffer. The 80 μl of aliquot of cell suspension(3.75×10⁵ cells/ml) was added to the assay plate and the cells were spundown by centrifuge (950 rpm, 20° C., 3 minutes).

The compounds of the examples were tested in the Human VR1 antagonistassay described above. The inhibition concentration 50% (IC₅₀) valuesare presented in the following table.

TABLE 1 Example # IC₅₀(nM) A1 93.5 A2 34.2 B1 590 C1 Not tested C2 667D1 74.1 D2 176 D3 403 D4 270 D5 331 D6 Not tested D7 31.9 D8 434 D9 Nottested D10 311 D11 501 D12 181 D13 31.8 D14 65.5 D15 254 Capsazepine237-455 (control)

Capsaicin Stimulation Assay

The capsaicin-induced changes in the intracellular calcium concentrationwere monitored using FDSS 6000 (Hamamatsu Photonics, Japan), afluorometric imaging system. The cell suspension in Krebs-Ringer HEPES(KRH) buffer (115 mM NaCl, 5.4 mM KCl, 1 mM MgSO₄, 1.8 mM CaCl₂, 11 mMD-Glucose, 25 mM HEPES, 0.96 mM Na₂HPO₄, pH 7.3) were pre-incubated withvarying concentrations of the test compounds or KRH buffer (buffercontrol) for 15 minutes at room temperature under the dark condition.Then capsaicin solution, which gives 300 nM in assay mixture, wasautomatically added to the assay plate by the FDSS 6000.

Acid Stimulation Assay

The acid-induced changes in the intracellular calcium concentration weremonitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometricimaging system. The cell suspension in resting buffer (HBSS supplementedwith 10 mM HEPES, pH 7.4) were pre-incubated with varying concentrationsof the test compounds or resting buffer (buffer control) for 15 minutesat room temperature under the dark condition. The cells wereautomatically added the stimulating solution (HBSS supplemented withMES, final assay buffer pH5.8) by the FDSS 6000. The IC₅₀ values of VR1antagonists were determined from the half of the increase demonstratedby buffer control samples after acidic stimulation.

Determination of Antagonist Activity

The monitoring of the changes in the fluorescence signals (λex=340nm/380 nm, λem=510-520 nm) was initiated at 1 minute prior to theaddition of capsaicin solution or acidic buffer and continued for 5minute. The IC₅₀ values of VR1 antagonists were determined from the halfof the increase demonstrated by buffer control samples after agoniststimulation.

Human VR1 Agonist Assay

The cells that express human VR1 receptors were maintained in cultureflask at 37° C. in an environment containing 5% CO₂ until use in theassay. The intracellular Ca²⁺ imaging assay to determine VR1 agonisticactivities were done by following procedures. The culture medium wasremoved from the flask and fura-2/AM fluorescent calcium indicator wasadded to the flask at a concentration of 5 μM in the medium. The flaskwas placed in CO₂ incubator and incubated for 1 hour. Then the cellsexpressing the human VR1 receptors were detached from the flask followby washing with phosphate buffer saline, PBS(−) and re-suspended inKrebs-Ringer HEPES buffer (KRH): 115 mM NaCl, 5.4 mM KCl, 1 mM MgSO₄,1.8 mM CaCl₂, 11 mM D-Glucose, 25 mM HEPES, 0.96 mM Na₂HPO₄, pH 7.3.

96-Well Format Assay

The test compound-induced changes in the intracellular calciumconcentration were monitored using FDSS 6000 (Hamamatsu Photonics,Japan), a fluorometric imaging system. The 80 μL of aliquot of cellsuspension (3.75×10⁵ cells/mL) in KRH buffer was distributed into the96-well plate, and then this assay plate was placed on the FDSS6000.Finally 20 μL of varying concentrations of the test compounds or KRHbuffer (buffer control) or 1 μM capsaicin (maximum response control)were automatically added to the assay plate by the FDSS 6000.

384-Well Format Assay

The 30 μL of aliquot of cell suspension (8×10⁵ cells/mL) in KRH bufferwas distributed into the 384-well plate, and then this assay plate wasplaced on the FDSS6000. Finally 15 μL of varying concentrations of thetest compounds or KRH buffer. (buffer control) or 2 μM capsaicin(maximum response control) were automatically added to the assay plateby the FDSS 6000.

Determination of Agonist Activity

The monitoring of the changes in the fluorescence signals (λex=340nm/380 nm, λem=510-520 nm) was initiated 1 min (96-well format) or 15seconds (384-well format) prior to the addition of test compounds andcontinued for 5 minute. The EC₅₀ values of compounds were determinedfrom the maximum response of test compounds. The E_(max) values weredetermined as a percentage of 1 μM (96-well format) or 2 μM (384-wellformat) capsaicin-induced response.

Chronic Constriction Injury Model (CCI Model)

Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba,Japan) were used. The chronic constriction injury (CCI) operation wasperformed according to the method described by Bennett and Xie (Bennett,G. J. and Xie, Y. K. Pain, 33:87-107, 1988). Briefly, animals wereanesthetized with sodium pentobarbital (64.8 mg/kg, i.p.) and the leftcommon sciatic nerve was exposed at the level of the middle of the thighby blunt dissection through biceps femoris. Proximal to the sciatic'strifurcation was freed of adhering tissue and 4 ligatures (4-0 silk)were tided loosely around it with about 1 mm space. Sham operation wasperformed as same as CCI surgery except for sciatic nerve ligation. Twoweeks after surgery, mechanical allodynia was evaluated by applicationof von Frey hairs (VFHs) to the plantar surface of the hind paw. Thelowest amount of force of VFH required to elicit a response was recordedas paw withdrawal threshold (PWT). VFH test was performed at 0.5, 1 and2 hr post-dosing. Experimental data were analyzed using Kruskal-Wallistest followed by Dunn's test for multiple comparisons or Mann-WhitneyU-test for paired comparison.

Mono-Iodoacetate (MIA)-Induced OA Model

Male 6-weeks-old Sprague-Dawley (SD, Japan SLC or Charles River Japan)rats were anesthetized with pentobarbital. Injection site (knee) of MIAwas shaved and cleaned with 70% EtOH. Twenty-five μl of MIA solution orsaline was injected in the right knee joint using a 29G needle. Theeffect of joint damage on the weight distribution through the right(damaged) and left (untreated) knee was assessed using an incapacitancetester (Linton Instrumentation, Norfolk, UK). The force exerted by eachhind limb was measured in grams. The weight-bearing (WB) deficit wasdetermined by a difference of weight loaded on each paw. Rats weretrained to measure the WB once a week until 20 days post MIA-injection.Analgesic effects of compounds were measured at 21 days after the MIAinjection. Before the compound administration, the “pre value” of WBdeficit was measured. After the administration of compounds, attenuationof WB deficits was determined as analgesic effects.

Complete Freund's Adjuvant (CFA) Induced Thermal and MechanicalHyperalgesia in Rats Thermal Hyperalgesia

Male 6-week-old SD rats were used. Complete Freund's adjuvant (CFA, 300pg of Mycobacterium Tuberculosis H37RA (Difco, MI) in 100 μL of liquidparaffin (Wako, Osaka, Japan)) was injected into the plantar surface ofhind paw of the rats. Two days after CFA-injection, thermal hyperalgesiawas determined by method described previously (Hargreaves et al., 1988)using the plantar test apparatus (Ugo-Basil, Varese, Italy). Rats wereadapted to the testing environment for at least 15 min prior to anystimulation. Radiant heat was applied to the plantar surface of hind pawand paw withdrawal latencies (PWL, seconds) were determined. Theintensity of radiant heat was adjusted to produce the stable PWL of 10to 15 seconds. The test compound was administered in a volume of 0.5 mLper 100 g body weight. PWL were measured after 1, 3 or 5 hours afterdrug administration.

Mechanical Hyperalgesia

Male 4-week-old SD rats were used. CFA (300 μg of MycobacteriumTuberculosis H37RA (Difco, MI) in 100 μL of liquid paraffin (Wako,Osaka, Japan)) was injected into the plantar surface of hind paw of therats. Two days after CFA-injection, mechanical hyperalgesia was testedby measuring paw withdrawal threshold (PWT, grams) to pressure using theanalgesy-Meter (Ugo-Basil, Varese, Italy). The animals were gentlyrestrained, and steadily increasing pressure was applied to the dorsalsurface of a hind paw via a plastic tip. The pressure required to elicitpaw withdrawal was determined. The test compound was administered in avolume of 0.5 mL per 100 g body weight. PWT were measured after 1, 3 or5 hours after drug administration.

Parallel Artificial Membrane Permeation Assay (PAMPA)

Experiments were performed in 96-well acceptor and donor plates. Such96-well system was described in Journal of Medicinal Chemistry, 1998,vol.41, No. 7, 1007-1010. 4% phosphatidylcholine and 1% stearic acid indodecane were used as artificial membrane material. The acceptor plate(96 well hydrophobic filter plate (MAIP N45, Millipore)) was prepared byadding 5 μL of artificial membrane material on the top of the filter andthe plate was filled with 250 μL of 2-(N-morpholino)ethanesulfonic acid(MES) buffered Hank's balanced salt solution (HBSS) (pH 6.5). The donorplate (Transport Receiver plate (MATRNPS50, Millipore)) was filled with300 μL of MES buffered HBSS (pH 6.5) containing 10 μM of the testcompounds. The acceptor plate was placed onto the donor plate to form a“sandwich” and was incubated at 30° C. for 2.5 hours. After theincubation period, acceptor, donor and initial donor solution(reference) were analyzed via LC-MS/MS. Data were reported as theeffective permeability value in cm×10⁶/sec and the membrane retentionvalue.

Human Dofetilide Binding

Cell paste of HEK-293 cells expressing the HERG product can be suspendedin 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25° C. with2 M HCl containing 1 mM MgCl₂, 10 mM KCl. The cells were homogenizedusing a Polytron homogenizer (at the maximum power for 20 seconds) andcentrifuged at 48,000 g for 20 minutes at 4° C. The pellet wasresuspended, homogenized and centrifuged once more in the same manner.The resultant supernatant was discarded and the final pellet wasresuspended (10-fold volume of 50 mM Tris buffer) and homogenized at themaximum power for 20 seconds. The membrane homogenate was aliquoted andstored at −80° C. until use. An aliquot was used for proteinconcentration determination using a Protein Assay Rapid Kit and ARVO SXplate reader (Wallac). All the manipulation, stock solution andequipment were kept on ice at all time. For saturation assays,experiments were conducted in a total volume of 200 μl. Saturation wasdetermined by incubating 20 μl of [³H]-dofetilide and 160 μl of membranehomogenates (20-30 μg protein per well) for 60 min at room temperaturein the absence or presence of 10 μM dofetilide at final concentrations(20 μl) for total or nonspecific binding, respectively. All incubationswere terminated by rapid vacuum filtration over polyetherimide (PEI)soaked glass fiber filter papers using Skatron cell harvester followedby two washes with 50 mM Tris buffer (pH 7.5 at 25° C.). Receptor-boundradioactivity was quantified by liquid scintillation counting usingPackard LS counter.

For the competition assay, compounds were diluted in 96 wellpolypropylene plates as 4-point dilutions in semi-log format. Alldilutions were performed in DMSO first and then transferred into 50 mMTris buffer (pH 7.5 at 25° C.) containing 1 mM MgCl₂, 10 mM KCl so thatthe final DMSO concentration became equal to 1%. Compounds weredispensed in triplicate in assay plates (4 μl). Total binding andnonspecific binding wells were set up in 6 wells as vehicle and 10 μMdofetilide at final concentration, respectively. The radioligand wasprepared at 5.6× final concentration and this solution was added to eachwell (36 μl). The assay was initiated by addition of YSi poly-L-lysineScintillation Proximity Assay (SPA) beads (50 μl, 1 mg/well) andmembranes (110 μl, 20 μg/well). Incubation was continued for 60 min atroom temperature. Plates were incubated for a further 3 hours at roomtemperature for beads to settle. Receptor-bound radioactivity wasquantified by counting Wallac MicroBeta plate counter.

I_(HERG) Assay

HEK 293 cells which stably express the HERG potassium channel were usedfor electrophysiological study. The methodology for stable transfectionof this channel in HEK cells can be found elsewhere (Z. Zhou et al.,1998, Biophysical Journal, 74, pp 230-241). Before the day ofexperimentation, the cells were harvested from culture flasks and platedonto glass coverslips in a standard Minimum Essential Medium (MEM)medium with 10% Fetal Calf Serum (FCS). The plated cells were stored inan incubator at 37° C. maintained in an atmosphere of 95% O₂/5% CO₂.Cells were studied between 15-28 hrs after harvest.

HERG currents were studied using standard patch clamp techniques in thewhole-cell mode. During the experiment the cells were superfused with astandard external solution of the following composition (mM); NaCl, 130;KCl, 4; CaCl₂, 2; MgCl₂, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH.Whole-cell recordings was made using a patch clamp amplifier and patchpipettes which have a resistance of 1-3 MOhm when filled with thestandard internal solution of the following composition (mM); KCl, 130;MgATP, 5; MgCl₂, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only thosecells with access resistances below 15 MΩ and seal resistances >1 GΩ wasaccepted for further experimentation. Series resistance compensation wasapplied up to a maximum of 80%. No leak subtraction was done. However,acceptable access resistance depended on the size of the recordedcurrents and the level of series resistance compensation that can safelybe used. Following the achievement of whole cell configuration andsufficient time for cell dialysis with pipette solution (>5 min), astandard voltage protocol was applied to the cell to evoke membranecurrents. The voltage protocol is as follows. The membrane wasdepolarized from a holding potential of −80 mV to +40 mV for 1000 ms.This was followed by a descending voltage ramp (rate 0.5 mV msec⁻¹) backto the holding potential. The voltage protocol was applied to a cellcontinuously throughout the experiment every 4 seconds (0.25 Hz). Theamplitude of the peak current elicited around −40 mV during the ramp wasmeasured. Once stable evoked current responses were obtained in theexternal solution, vehicle (0.5% DMSO in the standard external solution)was applied for 10-20 min by a peristalic pump. Provided there wereminimal changes in the amplitude of the evoked current response in thevehicle control condition, the test compound of either 0.3, 1, 3, 10 μMwas applied for a 10 min period. The 10 min period included the timewhich supplying solution was passing through the tube from solutionreservoir to the recording chamber via the pump. Exposing time of cellsto the compound solution was more than 5 min after the drugconcentration in the chamber well reached the attempting concentration.There was a subsequent wash period of a 10-20 min to assessreversibility. Finally, the cells were exposed to high dose ofdofetilide (5 μM), a specific IKr blocker, to evaluate the insensitiveendogenous current.

All experiments were performed at room temperature (23±1° C.). Evokedmembrane currents were recorded on-line on a computer, filtered at 500-1KHz (Kessel −3 dB) and sampled at 1-2 KHz using the patch clampamplifier and a specific data analyzing software. Peak currentamplitude, which occurred at around −40 mV, was measured off line on thecomputer.

The arithmetic mean of the ten values of amplitude was calculated undervehicle control conditions and in the presence of drug. Percent decreaseof I_(N) in each experiment was obtained by the normalized current valueusing the following formula: I_(N)=(1−I_(D)/I_(D))×100, where I_(D) isthe mean current value in the presence of drug and I_(C) is the meancurrent value under control conditions. Separate experiments wereperformed for each drug concentration or time-matched control, andarithmetic mean in each experiment is defined as the result of thestudy.

Drug-Drug Interaction Assay

This method essentially involves determining the percent inhibition ofproduct formation from fluorescence probe at 3 μM of the each compound.

More specifically, the assay is carried out as follows. The compoundswere pre-incubated with recombinant CYPs, 100 mM potassium phosphatebuffer and fluorescence probe as substrate for 5 min. Reaction wasstarted by adding a warmed NADPH generating system, which consist of 0.5mM NADP (expect; for 2D6 0.03 mM), 10 mM MgCl₂, 6.2 mM DL-Isocitric acidand 0.5 U/ml Isocitric Dehydrogenase (ICD). The assay plate wasincubated at 37° C. (expect; for 1 A2 and 3A4 at 30° C.) and takingfluoresce reading every minutes over 20 to 30 min.

Data calculations were preceded as follows;

-   1. The slope (Time vs. Fluorescence units) was calculated at the    linear region-   2. The percentage of inhibition in compounds was calculated by the    equation

{(v _(o) −v _(i))/v_(o)}×100=% inhibition

Wherein

v_(o)=rate of control reaction (no inhibitor)

v_(i)=rate of reaction in the presence of compounds.

TABLE 2 Condition for drug-drug interaction assay. 1A2 2C9 2C19 2D6 3A4Substrate Vivid MFC Vivid AMMC Vivid blue (Gentest) blue (Gentest) red(Aurora) (Aurora) (Aurora) Substrate 10 30 10  1 2 (μM) Enzyme 50 50  550 5 (pmol) EX./Em (λ) 408/465 408/535 408/465 400/465 530/595

Intrinsic Clearance

Test compounds (1 μM) were incubated with 1 mM MgCl₂, 1 mM NADP+, 5 mMisocitric acid, 1 U/mL isocitric dehydrogenase and 0.8 mg/mL HLM (humanliver microsomes) in 100 mM potassium phosphate buffer (pH 7.4) at 37°C. on a number of 384-well plates. At several time points, a plate wasremoved from the incubator and the reaction was terminated with twoincubation volumes of acetonitrile. The compound concentration insupernatant was measured by LC/MS/MS system. The intrinsic clearancevalue (Cl_(int)) was calculated using following equations:

Cl _(int)(μl/min/mg protein)=(k×incubation volume)/Protein concentration

k(min⁻¹)=−slope of In(concentration vs. time)

Drug Substance

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminum, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

A pharmaceutically acceptable salt of a compound of formula (I) may bereadily prepared by mixing together solutions of the compound of formula(I) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in thesalt may vary from completely ionized to almost non-ionized.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, EtOH. Theterm ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, polymorphs, prodrugs, and isomers thereof(including optical, geometric and tautomeric isomers) as hereinafterdefined and isotopically-labeled compounds of formula (I).

As stated, the invention includes all polymorphs of the compounds offormula (I) as hereinbefore defined.

Also within the scope of the invention are so-called ‘prodrugs’ of thecompounds of formula (I). Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further information on the use of prodrugs may be found in ‘Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and WStella) and ‘Bioreversible Carriers in Drug Design’, Pergamon Press,1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by HBundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include:

-   (i) where the compound of formula (I) contains an alcohol    functionality (—OH), an ether thereof, for example, replacement of    the hydrogen with (C₁-C₆)alkanoyloxymethyl; and-   (ii) where the compound of formula (I) contains a primary or    secondary amino functionality (—NH₂ or —NHR where R is not H), an    amide thereof, for example, replacement of one or both hydrogens    with (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Finally, certain compounds of formula (I) may themselves act as prodrugsof other compounds of formula (I).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (I)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where the compound contains, for example, a ketoor oxime group, an aromatic moiety or a heteroaromatic ring includingnitrogen of more than two, tautomeric isomerism (‘tautomerism’) canoccur. It follows that a single compound may exhibit more than one typeof isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor, or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994).

The present invention, includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. Examples of isotopes suitable for inclusion in thecompounds of the invention include isotopes of hydrogen, such as ²H and³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine,such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, andsulphur, such as ³⁵S. Certain isotopically-labelled compounds of formula(I), for example, those incorporating a radioactive isotope, are usefulin drug and/or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection. Substitution with heavier isotopes such asdeuterium, i.e. ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements, and hence may be preferred insome circumstances. Substitution with positron emitting isotopes, suchas ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, or spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term “excipient” is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in ‘Remington'sPharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films (including muco-adhesive), ovules,sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, EtOH, polyethyleneglycol, propylene glycol, methylcellulose, or a suitable oil, and one ormore emulsifying agents and/or suspending agents. Liquid formulationsmay also be prepared by the reconstitution of a solid, for example, froma sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1wt % to 80 wt % of the dosage form, more typically from 5 wt % to 60 wt% of the dosage form. In addition to the drug, tablets generally containa disintegrant. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinised starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation.

Suitable binders include microcrystalline cellulose, gelatin, sugars,polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone,pregelatinised starch, hydroxypropyl cellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents, such as lactose(monohydrate, spray-dried monohydrate, anhydrous and the like),mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 wt % to 5 wt % of the tablet, and glidants may comprise from 0.2 wt% to 1 wt % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 wt % to 10 wt %, preferably from 0.5 wt % to 3 wt %of the tablet.

Other possible ingredients include anti-oxidants, colorants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 wt % toabout 90 wt % binder, from about 0 wt % to about 85 wt % diluent, fromabout 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt % toabout 10 wt % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in “Pharmaceutical Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,N.Y, 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to beimmediate and/or modified controlled release. Modified releaseformulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Verma et al, PharmaceuticalTechnology On-line, 25(2), 1-14 (2001). The use of chewing gum toachieve controlled release is described in WO 00/35298.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include .intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous.

Suitable devices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or aspowdered a dried form to be used in conjunction with a suitable vehiclesuch as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents. Formulations for use with needle-freeinjection administration comprise a compound of the invention inpowdered form in conjunction with a suitable vehicle such as sterile,pyrogen-free water.

Formulations for parenteral administration may be formulated to beimmediate and/or modified controlled release. Modified releaseformulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release. Thus compounds of the invention may beformulated as a solid, semi-solid, or thixotropic liquid foradministration as an implanted depot providing modified release of theactive compound. Examples of such formulations include drug-coatedstents and PGLA microspheres.

Topical Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958 by Finninand Morgan (October 1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Inhaled/Intranasal Administration

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, EtOH, aqueous EtOH, or a suitable alternative agent fordispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified controlled release using, for example,poly(DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 1 μg to 10 mg of the compound offormula (I). The overall daily dose will typically be in the range 1 μgto 10 mg which may be administered in a single dose or, more usually, asdivided doses throughout the day.

Rectal/Intravaginal Administration

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Other Technologies

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Dosage

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.1 mg to 3000 mg,preferably from 1 mg to 500 mg, depending, of course, on the mode ofadministration. For example, oral administration may require a totaldaily dose of from 0.1 mg to 3000 mg, preferably from 1 mg to 500 mg,while an intravenous dose may only require from 0.1 mg to 1000 mg,preferably from 0.1 mg to 300 mg. The total daily dose may beadministered in single or divided doses.

These dosages are based on an average human subject having a weight ofabout 65 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

A VR1 antagonist may be usefully combined with another pharmacologicallyactive compound, or with two or more other pharmacologically activecompounds, particularly in the treatment of pain. For example, a VR1antagonist, particularly a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as defined above,may be administered simultaneously, sequentially or separately incombination with one or more agents selected from:

-   -   an opioid analgesic, e.g. morphine, heroin, hydromorphone,        oxymorphone, levorphanol, levallorphan, methadone, meperidine,        fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,        hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine or        pentazocine;    -   a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,        diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,        flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,        ketorolac, meclofenamic acid, mefenamic acid, meloxicam,        nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,        oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,        tolmetin or zomepirac;    -   a barbiturate sedative, e.g. amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal or thiopental;    -   a benzodiazepine having a sedative action, e.g.        chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,        oxazepam, temazepam or triazolam;    -   an H₁ antagonist having a sedative action, e.g. diphenhydramine,        pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;    -   a sedative such as glutethimide, meprobamate, methaqualone or        dichloralphenazone;    -   a skeletal muscle relaxant, e.g. baclofen, carisoprodol,        chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;    -   an NMDA receptor antagonist, e.g. dextromethorphan        ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan        ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,        pyrroloquinoline quinine,        cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,        EN-3231 (MorphiDex®, a combination formulation of morphine and        dextromethorphan), topiramate, neramexane or perzinfotel        including an NR2B antagonist, e.g. ifenprodil, traxoprodil or        (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;    -   an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, or        4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)        quinazoline;    -   a tricyclic antidepressant, e.g. desipramine, imipramine,        amitriptyline or nortriptyline;    -   an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate        or valproate;    -   a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g.        (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);    -   a muscarinic antagonist, e.g oxybutynin, tolterodine,        propiverine, tropsium chloride, darifenacin, solifenacin,        temiverine and ipratropium;    -   a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;    -   a coal-tar analgesic, in particular paracetamol;    -   a neuroleptic such as droperidol, chlorpromazine, haloperidol,        perphenazine, thioridazine, mesoridazine, trifluoperazine,        fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,        quetiapine, sertindole, aripiprazole, sonepiprazole,        blonanserin, iloperidone, perospirone, raclopride, zotepine,        bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,        palindore, eplivanserin, osanetant, rimonabant, meclinertant,        Miraxion® or sarizotan;    -   a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist        (e.g. capsazepine);    -   a beta-adrenergic such as propranolol;    -   a local anaesthetic such as mexiletine;    -   a corticosteroid such as dexamethasone;    -   a 5-HT receptor agonist or antagonist, particularly a        5-HT_(1B/1D) agonist such as eletriptan, sumatriptan,        naratriptan, zolmitriptan or rizatriptan;    -   a 5-HT_(2A) receptor antagonist such as        R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol        (MDL-100907);    -   a cholinergic (nicotinic) analgesic, such as ispronicline        (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine        (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine        (ABT-594) or nicotine;    -   Tramadol®;    -   a PDEV inhibitor, such as        5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (sildenafil),        (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione        (IC-351 or tadalafil),        2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        (vardenafil),        5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,        3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1        H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;    -   an alpha-2-delta ligand such as gabapentin, pregabalin,        3-methylgabapentin,        (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,        (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (2S,4S)-4-(3-chlorophenoxy)proline,        (2S,4S)-4-(3-fluorobenzyl)-proline,        [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,        3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,        C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,        (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,        (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,        (3S,5R)-3-amino-5-methyl-nonanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid,        (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid,        (2S)-2-Amino-4-ethyl-2-methylhexanoic acid and        (2S)-2-aminomethyl-5-ethyl-heptanoic acid;    -   a cannabinoid;    -   metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;    -   a serotonin reuptake inhibitor such as sertraline, sertraline        metabolite demethylsertraline, fluoxetine, norfluoxetine        (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,        citalopram, citalopram metabolite desmethylcitalopram,        escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,        cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine        and trazodone;    -   a noradrenaline (norepinephrine) reuptake inhibitor, such as        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®),        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine;    -   a dual serotonin-noradrenaline reuptake inhibitor, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   an inducible nitric oxide synthase (iNOS) inhibitor such as        S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,        S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,        S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,        (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic        acid,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile;        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,        (2S,4R)-2-amino-4-[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3        pyridinecarbonitrile,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,

N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, orguanidinoethyldisulfide;

-   -   an acetylcholinesterase inhibitor such as donepezil;    -   a prostaglandin E₂ subtype 4 (EP4) antagonist such as        N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide        or        4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic        acid;    -   a leukotriene B4 antagonist; such as        1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic        acid (CP-105696),        5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric        acid (ONO-4057) or DPC-11870,    -   a 5-lipoxygenase inhibitor, such as zileuton,        6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone        (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),        1,4-benzoquinone (CV-6504);    -   a sodium channel blocker, such as lidocaine;    -   a 5-HT3 antagonist, such as ondansetron;        and the pharmaceutically acceptable salts and solvates thereof.

In as much as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically,comprises directions foradministration and may be provided with a so-called memory aid.

Examples

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all operations were carried out at roomor ambient temperature, that is, in the range of 18-25° C.; evaporationof solvent was carried out using a rotary evaporator under reducedpressure with a bath temperature of up to 60° C.; reactions weremonitored by thin layer chromatography (TLC) and reaction times weregiven for illustration only; melting points (mp) given were uncorrected(polymorphism may result in different melting points); the structure andpurity of all isolated compounds were assured by at least one of thefollowing techniques: TLC (Merck silica gel 60 F₂₅₄ precoated TLCplates), mass spectrometry, nuclear magnetic resonance spectra (NMR),infrared red absorption spectra (IR) or microanalysis. Yields were givenfor illustrative purposes only. Flash column chromatography was carriedout using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia aminobounded silica (Chromatorex, 30-50 uM) or Biotage amino bounded silica(35-75 μm, KP-NH) or Biotage silica (32-63 μm, KP-Sil). The purificationusing HPLC was performed by the following apparatus and conditions.Apparatus: UV-trigger preparative HPLC system, Waters (Column: XTerra MSC18, 5 urn, 19×50 mm or 30×50 mm), Detector: UV 254 nm Conditions:CH₃CN/0.05% HCOOH aqueous solution or CH₃CN/0.01% NH₃ aqueous solution;20 ml/min (19×50 mm) or 40 ml/min (30×50 mm) at ambient temperature.Microwave apparatus used in the reaction was Emrys optimizer (Personalchemistry). Optical rotation was measured by P-1020 (Jasco).Low-resolution mass spectral data (EI) were obtained on a Integrity(Waters) mass spectrometer. Low-resolution mass spectral data (ESI) wereobtained on a ZMD (Micromass) mass spectrometer. NMR data weredetermined at 270 MHz (JEOL JNMLA 270 spectrometer) or 300 MHz (JEOLJNMLA300 spectrometer) using deuterated chloroform (99.8% D) or DMSO(99.9% D) as solvent unless indicated otherwise, relative totetramethylsilane (TMS) as internal standard in parts per million (ppm);conventional abbreviations used were: s=singlet, d=doublet, t=triplet,q=quartet, quint=quintet, m=multiplet, br.=broad, etc. IR spectra weremeasured by a Shimazu infrared spectrometer (IR-470). Chemical symbolshave their usual meanings; by (boiling point), mp (melting point), L(liter(s)), ml (milliliter(s)), g (gram(s)), mg (milligram(s)), mol(moles), mmol (millimoles), eq. (equivalent(s)), quant. (quantitativeyield), sat. (saturated), aq (aqua). In the following Examples, “Me”means methyl and “Et” means ethyl.

Preparations

The following Preparations illustrate the preparation of certain Amineand Carboxylic Acid intermediates used to prepare the Exampleshereinbelow.

Amine 1: 4-(Aminomethyl)-5-chloro-2-methoxyphenol

The title amine was prepared by the method described in WO2005/123666.

Amine 2: 4-(Aminomethyl)-5-bromo-2-methoxyphenol

The title amine was prepared by the same procedure as Amine 1, usingN-bromosuccinimide instead of N-chlorosuccinimide. ¹H-NMR (300 MHz,DMSO-d6) δ ppm 3.79 (3H, s), 4.02 (2H, s), 7.04 (1H, s), 7.24 (1H, s),8.23 (3H, br s), 9.86 (1H, s).

MS(ESI) m/z: 217 (M+H—NH₂)⁺.

Amine 3: (R)-4-(1-Aminoethyl)-5-chloro-2-methoxyphenol

Step A-3A:(R)—N—((R)-1-(4-hydroxy-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide

To a THF (63 ml) solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (4.99g, 30.0 mmol, purchased from TCI) and(R)-(+)-2-methyl-2-propanesulfinylamide (4.00 g, 33.0 mmol),titanium(IV) ethoxide (63.0 ml, 0.30 mol) was added under a nitrogenatmosphere and the mixture was refluxed with stirring for 20 hours.After imine formation was confirmed with LC-MS, the mixture was cooledto r.t. and the imine solution was added dropwise to a suspension ofsodium borohydride (3.41 g, 90.1 mmol) in THF (50 mL) at 0° C. undernitrogene atmosphere. After stirring at room temperature for 3 hours,the reaction mixture was partitioned with water and ethanol, then themixture was stirred for 1 hour at room temperature. The mixture wasfiltered through a Celite pad, and the filtrate was evaporated andconcentrated in vacuo. The mixture was dissolved in EtOAc (500 ml),washed with 1N hydrochloric acid (300 ml), saturated aqueous sodiumbicarbonate (300 ml), and brine (300 ml), and the organic layer wasdried over sodium sulfate. Removal of the solvent gave a residue, whichwas chromatographed on a column of silica gel, eluting with EtOAc-hexane(1:1 to 3:1), to give the title compound (4.10 g, 50%) as a colorlesssyrup. ¹H NMR (270 MHz,CDCl₃) δ ppm 1.23 (9H, s), 1.49 (3H, d, J=6.6Hz), 3.36 (1H, m), 3.89 (3H, s), 4.40-4.60 (1H, m), 5.71 (1H, s), 6.87(3H, m).

MS (ESI) m/z: not observed M⁺ peak.

Step A-3B: (R)-4-(1-aminoethyl)-2-methoxyphenol hydrochloride

To(R)—N—((R)-1-(4-hydroxy-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide(4.10 g, 15.1 mmol) was added 10% hydrogen chloride in methanol (40 ml),and the resulting mixture was stirred at room temperature for 3 h. Thereaction mixture was evapolated and dried in vacuo to give the titlecompound (crude 6.75 g) as a white solid. This crude amine was used forthe next step without further purification. ¹H NMR (270 MHz,DMSO-d₆) δppm 1.48 (3H, d, J=6.6 Hz), 3.79 (3H, s), 4.27 (1 H, m), 6.79 (1H, d,J=8.5 Hz), 6.88 (1H, d, J=8.0 Hz), 7.17 (1H, s), 8.35 (3H, br.s), 9.18(1H, br.s). MS (ESI) m/z 151 (M+H—NH₂)⁺.

Step A-3C: (R)-4-(1-acetamidoethyl)-2-methoxyphenyl acetate

Acetic anhydride (8 ml, 80 mmol) was added to the solution of(R)-4-(1-aminoethyl)-2-methoxyphenol hydrochloride (crude 6.75 g) inpyridine (50 ml) and the resulting mixture stirred at room temperaturefor 3 hours. Removal of the solvent gave a residue, which waschromatographed on a column of silica gel, eluting with EtOAc-Hexane(1:1) and then MeOH-DCM (1:10), to give the title compound (2.86 g, 75%for 2 steps) as yellow syrup. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.49 (3H, d,J=6.6 Hz), 1.99 (3H, s), 2.31 (3H, s), 3.83 (3H, s), 5.12 (1H, m), 5.67(1H, m), 6.78-7.08 (3H, m). MS (ESI) m/z not observed M⁺ peak.

Step A-3D: (R)-4-(1-acetamidoethyl)-5-chloro-2-methoxyphenyl acetate)

N-Chlorosuccinimide (2.28 g, 17.1 mmol) was added to a solution of

(R)-4-(1-acetamidoethyl)-2-methoxyphenyl acetate (2.86 g, 11.4 mmol) inDMF (50 mL) and the mixture was stirred for 1 hour at 0° C. and then for15 hours at room temperature. The reaction mixture was poured ontoaqueous 20% sodium thiosulfate solution and extracted with DCM 3 times.The combined organic layer was dried over sodium sulfate, filtered andevaporated. The residue was chromatographed on a column of silica gel,eluting with EtOAc-Hexane (1:1) and then MeOH-DCM (1:10), to give abrown solid. The solid was washed with Et₂O and dried in vacuo to givethe title compound (2.40 g, 74%) as white solid. ¹H NMR (270 MHz,CDCl₃)δ ppm 1.51 (3H, d, J=7.2 Hz), 2.00 (3H, s), 2.30 (3H, s), 3.83 (3H, s),5.20-5.40 (1H, m), 5.91 (1H, m), 6.91 (1H, s), 7.06 (1H, s).

MS (ESI) m/z not observed M⁺ peak.

Step A-3E: (R)-4-(1-aminoethyl)-5-chloro-2-methoxyphenol hydrochloride

37% Hydrochloric acid (20 ml) was added to a solution of(R)-4-(1-acetamidoethyl)-5-chloro-2-methoxyphenyl acetate (2.40 g, 8.4mmol) in EtOH (80 ml) and the mixture was refluxed for 48 hours. Thereaction mixture was cooled to room temperature, washed with DCM 3times, and the aqueous layer was evaporated under reduced pressure. Theresidue was dissolved in diisopropyl ether and the precipitate wascollected by filtration. The solid was washed with DCM and dried invacuo to give the title compound (1.21 g, 60%) as white solid. ¹H NMR(300 MHz,DMSO-d₆) δ ppm 1.49 (3H, d, J=6.6 Hz), 3.82 (3H, s), 4.55 (1 H,m), 6.91 (1H, s), 7.54 (1H, s), 8.76 (3H, br.s), 9.87 (1H, br.s). MS(ESI) m/z not observed M⁺ peak.

Amine 4: (R)-1-(2-Chloro-4-methoxy-5-methylphenyl)ethanamine

Step A-4A: (R)—N—((R orS)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

To a THF (20.1 ml) solution of1-(2-chloro-4-methoxy-5-methylphenyl)ethanone (1.91 g, 9.6 mmol, Journalof the Chemical Society, 1946, 1866-1869) and(R)-(+)-2-methyl-2-propanesulfinylamide (1.28 g, 10.6 mmol),titanium(IV) ethoxide (20.1 ml, 96.0 mmol) was added in the sameprocedure described in preparation A-3A. The crude residue was appliedto a silica gel column chromatography and eluted with EtOAc-Hexane (1:4to 1:1) to furnish the title compounds (less polar, (R)-isomer, 1.38 g,47%) as colorless syrup and (more polar, (S)-isomer, 0.66 g, 23%) aswhite solid. The stereochemistry was determined by X-ray analysis.

(R)-Isomer

¹H NMR (300 MHz, CDCl₃) δ 1.23 (9H, s), 1.48 (3H, d, J=7.4 Hz), 2.18(3H, s), 3.48 (1H, br d, J=3.6 Hz), 3.81 (3H, s), 4.89 (1H, m), 6.80(1H, s), 7.16 (1H, s).

MS (ESI): m/z 304 (M+H)⁺.

(S)-Isomer

¹H NMR (300 MHz, CDCl₃) δ 1.20 (9H, s), 1.52 (3H, d, J=6.7 Hz), 2.17(3H, s), 3.30 (1H, br d, J=4.4 Hz), 3.81 (3H, s), 4.94 (1 H, m), 6.80(1H, s), 7.16 (1H, s).

MS (ESI): m/z 304 (M+H)⁺.

Step A-4B: (R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethanaminehydrochloride

To((R)—N—((R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide(0.64 g, 2.1 mmol) was added 10% hydrogen chloride in methanol (10 ml),and the resulting mixture was stirred at room temperature for 3 h. Thereaction mixture was evaporated and dried in vacuo to give the titlecompound (crude 0.63 g) as white solid. This amine was used for the nextstep without further purification.

¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.47 (3H, d, J=7.4 Hz), 2.14 (3H, s),3.82 (3H, s), 4.59 (1H, m), 7.06 (1H, s), 7.56 (1H, s), 8.61 (3H, br s).MS (ESI) m/z 183 (M+H—NH₂)⁺.

Amine 5: (S)-1-(2-Chloro-4-methoxy-5-methylphenyl)ethanamine

To ((R)—N—((S)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (0.66 g, 2.2 mmol) was added 10% hydrogen chloridein methanol (10 ml), and the resulting mixture was stirred at roomtemperature for 3 h. The reaction mixture was evaporated and dried invacuo to give the title compound (crude 0.66 g) as white solid. Thisamine was used for the next step without further purification.

¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.47 (3H, d, J=7.4 Hz), 2.14 (3H, s),3.82 (3H, s), 4.59 (1 H, m), 7.06 (1 H, s), 7.56 (1 H, s), 8.61 (3H, brs). MS (ESI) m/z 183 (M+H—NH₂)⁺.

Amine 6: 4-(Aminomethyl)-5-fluoro-2-methylphenol hydrochloride

Step A-6A: 2-Fluoro-4-hydroxy-5-methylbenzaldehyde

To a solution of 5-fluoro-2-methylphenol (630 mg, 5 mmol) indichloromethane (5 ml) was added titanium chloride (1890 mg, 10 mmol)dropwise at 0° C. and then (dichloromethyl)-methyl ether (689 mg, 6mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour,quenched with ice (50 g) and extracted with ethyl acetate. The organiclayer was separated, dried over Na2SO4, concentrated and applied to asilica gel column, eluting with hexane/ethyl acetate (10:1), to furnishthe title compound (545 mg, 71% yield) as a white solid. ¹H NMR (270MHz, CDCl₃) δ 2.25 (3H, s), 6.04 (1H, brs), 6.60 (1H, d, J=11.2 Hz),7.66 (1H, d, J=7.9 Hz), 10.18 (1H, s).

Step A-6B:N-(2-Fluoro-4-hydroxy-5-methylbenzyl)-2-methylpropane-2-sulfinamide

The product of Step A-6A (400 mg, 2.6 mmol) was converted to the titlecompound (547 mg, 81% yield) in same procedure described in Step A-3A.

¹H NMR (300 MHz, CDCl₃) δ 1.24 (9H, s), 2.08 (3H, s), 3.60-3.66 (1H, m),4.11-4.32 (2H, m), 6.29 (1H, d, J=11.7 Hz), 6.95 (1H, d, J=8.8 Hz), 7.70(1H, brs). MS (ESI): m/z 260 (M+H)+.

Step A-6C: 4-(Aminomethyl)-5-fluoro-2-methylphenol hydrochloride

A solution of the product of Step A-6B (547 mg, 2.11 mmol) in4M-hydrochloride-methanol solution (10 ml) was stirred at roomtemperature for 1 hour. The mixture was concentrated under reducedpressure to furnish the title compound (454 mg, quant.) as a whitesolid. ¹H NMR (270 MHz, DMSO-d₆) δ 2.07 (3H, s), 3.85-3.90 (2H, m),6.66-6.75 (1H, m), 7.25 (1H, d, J=8.6 Hz), 8.36 (2H, brs), 10.21 (1H,brs). MS (ESI): m/z 154 (M−H)−.

Amine 7: (2-Chloro-4-methoxy-5-methylphenyl)methanamine

Step A-7A: 2-(2-chloro-4-methoxy-5-methylbenzyl)isoindoline-1,3-dione

To a solution of 5-chloro-2-methylanisole (200 mg, 1.28 mmol, purchasedfrom APOLLO) and (1,3-dioxoisoindolin-2-yl)methyl2,2,2-trichloroacetimidate (411 mg, 1.28 mmol, Synthesis, 2003, 7,1065-1070) in DCM (30 mL) was added trimethylsilyltrifluoromethansulfonate (14.2 mg, 0.064 mmol) at room temperature undernitrogen. After stirring for 3 hours at room temperature, the reactionmixture was quenched with solid potassium carbonate and evaporated. Theresidue was chromatographed on a column of silica gel, eluting withEtOAc-Hexane=1:5 to 1:3, to give the title compound (174 mg, 43%) aswhite solid. ¹H NMR (300 MHz,CDCl₃) δ ppm 2.11 (3H, s), 3.79 (3H, s),4.91 (2H, s), 6.81 (1H, s), 7.05 (1H, s), 7.60-7.80 (2H, m), 7.80-8.00(2H, m). MS (ESI) m/z not observed M⁺ peak.

Step A-7B: (2-chloro-4-methoxy-5-methylphenyl)methanamine

2-(2-Chloro-4-methoxy-5-methylbenzyl)isoindoline-1,3-dione (174 mg, 0.55mmol) was dissolved in MeOH (30 ml) and hydrazine hydrate (111 mg, 2.21mmol) and then heated under reflux for 1 hour. The solvent was removedin vacuo and the precipitate was filtered off. The filtrate wasevaporated to give a residue, which was chromatographed on a column ofsilica gel eluting with MeOH-DCM (1:10) to give the title compound (130mg, 100%) as white solid. ¹H NMR (270 MHz,DMSO-d₆) δ ppm 2.12 (3H, s),3.38 (2H, br s), 3.69 (2H, s), 3.78 (3H, s), 6.94 (1H, s), 7.29 (1H, s).MS (ESI) m/z 169 (M+H—NH₂)⁺

Amine 8: {4-[(1R)-1-Aminoethyl]phenyl}methanol hydrochloride

Step A-8A: Methyl 4-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoate

tert-Butyl[(1R)-1-(4-bromophenyl)ethyl]carbamate (1784 mg, 5.9 mmol) wasconverted to the title compound (378 mg, 23% yield) in same proceduredescribed in Step C-1A

¹H NMR (300 MHz, CDCl₃) δ 1.42-1.59 (12H, m), 3.91 (3H, s), 4.82-4.86(2H, m), 7.37 (2H, d, J=8.1 Hz), 8.00 (2H, d, J=8.1 Hz).

Step A-8B: tert-Butyl}(1R)-1-[4-(hydroxymethyl)phenyl]ethyl}carbamate

To a solution of the product of Step A-8A (375 mg, 1.34 mmol) in Et₂O(16 ml) and THF (4 ml) was added lithium aluminum hydride (102 mg, 2.68mmol) portionwise at −15° C. After 15 minutes, the mixture was stirredat 20° C. for 1 hour. The mixture was diluted with THF (40 ml) andquenched with sodium sulfate.10 hydrate and brine. The organic layer wasseparated and concentrated to furnish the title compound (417 mg,quant.) as colorless oil. ¹H NMR (270z, CDCl₃) δ1.42-1.59 (12H, m),3.70-3.75 (1H, m), 4.68 (2H, s), 4.68-4.80 (1H, m), 7.27-7.36 (4H, m).

Step A-8C: {4-1(1R)-1-Aminoethyl]phenyl}methanol hydrochloride

A solution of the product of Step A-8B (416 mg, 1.3 mmol) in4M-hydrochloride-methanol solution was stirred at room temperature for 2hours, then concentrated hydrochloride aqueous solution (0.5 ml) wasadded. After 3 hours, the solvent was removed in vacuo and co-evaporatedwith toluene to furnish the title compound (322 mg, quant.) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.49 (3H, d, J=6.6 Hz), 3.36-3.40(1H, m), 4.36-4.38 (1H, m), 4.50 (2H, s), 7.35 (2H, d, J=7.3 Hz), 7.45(2H, d, J=8.1 Hz), 8.49 (2H, brs).

Amine 9: [4-(1-Aminoethyl)-5-fluoro-2-methylphenyl]methanolhydrochloride

Step A-9A:N-[1-(4-Bromo-2-fluoro-5-methylphenyl)ethyl]-2-methylpropane-2-sulfinamide

1-(4-Bromo-2-fluoro-5-methylphenyl)ethanone (1.78 g, 7.7 mmol) wasconverted to the title compound (1323 mg, 51% yield) in the proceduredescribed in Step A-3A. ¹H NMR (270 MHz, CDCl₃) δ 1.22 (9H, s), 1.51(3H, d, J=6.6 Hz), 2.36 (3H, s), 3.49-3.52 (1H, m), 4.63-4.73 (1H, m),7.19-7.27 (2H, m). MS (ESI): m/z 336, 338 (M+H)+.

Step A-9B: Methyl4-{1-[(tert-butylsulfinyl)amino]ethyl}-5-fluoro-2-methylbenzoate

The product of Step A-9A (700 mg, 2.1 mmol) was converted to the titlecompound (579 mg, 88% yield) in the procedure described in Step C-1A.

¹H NMR (300 MHz, CDCl₃) δ 1.23 (9H, s), 1.54 (3H, d, J=6.6 Hz), 2.57(3H, s), 3.48-3.58 (1H, m), 3.89 (3H, s), 4.72-4.76 (1H, m), 7.22 (1H,d, J=7.3 Hz), 7.61 (1H, d, J=11.0 Hz). MS (ESI): m/z 316 (M+H)+.

Step A-9C:N-{1-[2-Fluoro-4-(hydroxymethyl)-5-methylphenyl]ethyl}-2-methylpropane-2-sulfinamide

To a solution of the product of Step A-9B (367 mg, 1.16 mmol) in Et₂O(10 ml) was added lithium aluminum hydride (88 mg, 2.33 mmol) at −78° C.The mixture was stirred at −78° C. for 2 hours and at 0° C. for 1 hour.The reaction was quenched with brine (3 ml), and diluted with ethylacetate (50 ml). The organic layer was dried over sodium sulfate andconcentrated to furnish the title compound (380 mg, quant.) as colorlessoil. ¹H NMR (270 MHz, CDCl₃) δ 1.22 (9H,s), 1.51 (3H, d, J=6.6 Hz), 1.79(1H, t, J=5.6 Hz), 2.27 (3H, s), 3.52-3.54 (1H, m), 4.63-4.73 (3H, m),7.09-7.13 (2H, m). MS (ESI): m/z 288 (M+H)+.

Step A-9D: [4-(1-Aminoethyl)-5-fluoro-2-methylphenyl]methanolhydrochloride

A solution of the product of Step A-9E (380 mg, 1.1 mmol) in 4Nhydrochloride-methanol solution (5 ml) was stirred at room temperaturefor 16 hours. The solvent was removed in vacuo and co-evaporated withtoluene to furnish the title compound (363 mg, quant.) as a colorlessoil. ¹H NMR (300 MHz, DMSO-d₆) δ 1.50 (3H, d, J=7.3 Hz), 2.19 (3H, s),4.42-4.57 (3H, m), 7.14-7.39 (2H, m), 8.84 (1H, brs).

Amine 10: (R)-4(1-Aminoethyl)-2-methoxyphenol

The title amine was prepared by the method described in Sankyo KenkyushoNenpo, 1990, 42, 41-64, or is commercially available from NetChem.

Carboxylic Acid 1: 6-tert-Butyl-2-naphthoic acid

Step C-1A: Methyl 6-tent-butyl-2-naphthoate

A mixture of 2-bromo-6-tert-butylnaphthalene (980 mg, 3.72 mmol),palladium acetate (84 mg, 0.37 mmol), 1,3-bis(diphenylphophino)propane(153 mg, 0.37 mmol) and triethylamine (1.56 ml, 11.2 mmol) in MeOH (6ml) and DMF (10 ml) was heated at 80° C. under carbon monooxide gaspressure (balloon) for 15 hours. After cooling to ambient temperature,the mixture was diluted with EtOAc-toluene (8:1) (160 ml) and filteredthrough a pad of celite. The filtrate and washings were washed withwater, then brine, dried over sodium sulfate and evaporated in vacuo togive the crude product which was purified through silica gel columnchromatography, eluting with hexane/EtOAc (10:1), to furnish the titlecompound as colorless oil (843 mg, 94%). ¹H NMR (CDCl₃): δ 1.43 (9H, s),3.97 (3H, s), 7.61-7.67 (1 H, m), 7.79-7.93 (3H, m), 8.01-8.07 (1H, m),8.57 (1H, br, s).

Step C-1B: 6-tert-Butyl-2-naphthoic acid

A mixture of methyl 6-tert-butyl-2-naphthoate (843 mg, 3.48 mmol) and 2Msodium hydroxide solution (6.96 mmol, 3.48 mmol) in MeOH (30 ml) washeated at 60° C. for 3 hours. After cooling to ambient temperature, thesolvent was evaporated in vacuo and the residue was acidified to pH 2with 2M hydrochloric aqueous solution. The aqueous layer was extractedwith EtOAc and the combined solution was washed with brine, dried oversodium sulfate and evaporated in vacuo to give the crude product whichwas recrystallized from EtOAc and hexane to furnish the title compoundas a white solid (614 mg, 77%). ¹H NMR (DMSO-d₆): δ 1.39 (9H, s),7.70-7.76 (1H, m), 7.90-8.08 (4H, m), 8.55 (1H, br, s), 13.00 (1H, br,s).

Carboxylic Acid 2: 6-tert-Butylquinoline-2-carboxylic acid

Step C-2A: 6-tert-Butylquinoline 1-oxide

A mixture of 6-tert-butylquinoline (400 mg, 2.16 mmol, Journal of theIndian Chemical Society, 1998, 823) and mCPBA (639 mg, 2.59 mmol) inchloroform (10 ml) was stirred for 2 hours at room temperature. Themixture was concentrated and the crude residue was applied to a silicagel (NH silica) column and eluted with DCM/MeOH (20:1) to furnish thetitle compound (433 mg, quant.) as pale orange oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43 (9H,s) 7.26-7.30 (1H, m), 7.73 (1H, d,J=8.1 Hz), 7.78 (1H, s), 7.85 (1H, dd, J=1.5, 8.8 Hz), 8.49 (1H, d,J=5.9 Hz), 8.67 (1H, d, J=8.8 Hz). MS (ESI): m/z 202 (M+H)+.

Step C-2B: 6-tert-Butylquinoline-2-carbonitrile

A mixture of 6-tert-butylquinoline 1-oxide (310 mg, 1.54 mmol),trimethylsilylcyanide (458 mg, 4.62 mmol), and trimethylamine (312 mg,3.08 mmol) in acetonitrile (3 ml) was stirred for 15 minutes at 120° C.under microwave irradiation. The mixture was applied to a silica gelcolumn and eluted with hexane/EtOAc (20:1) to furnish the title compound(295 mg, 91% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.44(9H, s), 7.68 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.2 Hz), 7.94 (1H, d,J=2.2, 8.8 Hz), 8.11 (1H, d, J=8.8 Hz), 8.26 (1 H, d, J=8.8 Hz). MS(ESI): m/z 211 (M+H)+.

Step C-2C: 6-tert-Butylquinoline-2-carboxylic acid

A solution of 6-tert-butylquinoline-2-carbonitrile (295 mg, 1.40 mmol)and 2M-aqueous sodium hydroxide (3 ml) in EtOH (4.5 ml) was stirred for4 hours at reflux. The mixture was diluted with water (10 ml),neutralized by 2M-aqueous hydrochloride and extracted with EtOAc (30ml). The organic layer was dried over sodium sulfate, filtrated, andconcentrated in vacuo to furnish the title compound (313 mg, quant.) asa white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.40 (9H, s), 7.93-7.97 (2H, m), 8.01-8.11(2H, m), 8.41 (1H, d, J=8.1 Hz). MS (ESI): m/z 230 (M+H)+.

Carboxylic Acid 3: 7-(Trifluoromethyl)quinoline-3-carboxylic acid

This compound was synthesized according to the process described in theJournal of Medicinal Chemistry (1979), 22(7), 816-23.

Carboxylic Acid 4: 2-tert-Butylquinoline-6-carboxylic acid

Step C-4A: Methyl 2-tert-butylquinoline-6-carboxylate

To a THF (20 ml) solution of methyl quinoline-6-carboxylate (984 mg,5.26 mmol, J.O.C., 2002, 67, 7890) was added t-butylmagnesium chloridein THF (15.8 ml, 1M solution) dropwise at −78° C. over 30 min. Themixture was stirred at −78° C. for 30 minutes and at −40° C. for 30minutes, then at room temperature for 1 hour. The reaction was quenchedwith saturated ammonium chloride aqueous solution (100 ml) and extractedwith ethyl acetate (100 ml×2) which was dried over sodium sulfate. Then,filtration and evaporation gave a yellow oil, which was dissolved in THF(50 ml) and manganese dioxide (1.83 g 15.8 mmol) was added. After themixture was stirred at room temperature for 2.5 hours, the precipitatewas removed through a pad of celite and washed with ethyl acetate. Thefiltrate was concentrated and purified through silica gel columnchromatography, eluting with Hexane/Ethyl acetate (20:1), to furnish thetitle compound (348 mg, 27% yield) as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 1.48 (9H, s), 3.99 (3H, s), 7.59 (1H, d, J=8.8 Hz), 8.08 (1H,d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.26 (1H, dd, J=2.2, 8.8 Hz), 8.55(1H, d, J=2.2 Hz). MS (ESI): m/z 244 (M+H)+.

Step C-4B: 2-tert-Butylquinoline-6-carboxylic acid

To a solution of methyl 2-tert-butylquinoline-6-carboxylate (347 mg,1.43 mmol) in methanol (4 ml) and THF (4 ml) was added 2N aqueous sodiumhydroxide (2 ml) at room temperature. The mixture was stirred at roomtemperature for 1.5 hours, then evaporated, diluted with water (5 ml),and neutralized to pH 5-6 by 2M aqueous hydrochloride. The formedprecipitate was collected and washed with water to furnish the titlecompound (282 mg, 86% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃)δ1.49 (9H, s), 7.62 (1H, d, J=8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.20 (1H,d, J=8.8 Hz), 8.31-8.34 (1H, m), 8.64-8.66 (1H, m). MS (ESI): m/z 230(M+H)+.

Carboxylic Acid 5:2-(2,2,2-Trifluoro-1,1-dimethylethyl)quinoline-6-carboxylic acid

Step C-5A: 6-Bromo-N-methoxy-N-methylquinoline-2-carboxamide

A DMF (1 ml) solution of 6-bromoquinoline-2-carboxylic acid (4000 mg,15.9 mmol, US2005165049A1), triethylamine (6.64 ml, 47.6 mmol),N,O-dimethylhydroxyamine hydrochloride (1860 mg, 19.0 mmol) and HBTU(6620 mg, 17.5 mmol) was treated in the procedure described in Example1, Step G. The crude residue was applied to a silica gel column andeluted with hexane/ethyl acetate (4:1) to furnish the title compound(4.29 g, 92% yield) as an orange solid. ¹H NMR (300 MHz, CDCl₃) δ 3.47(3H, s), 3.80 (3H, s), 7.68-7.80 (1H, brs), 7.81-7.85 (1H, m), 8.00-8.06(2H, m), 8.17 (1H, d, J=8.1 Hz). MS (ESI): m/z 295, 297 (M+H)⁺.

Step C-5B: 1-(6-Bromoquinolin-2-yl)ethanone

To a solution of 6-bromo-N-methoxy-N-methylquinoline-2-carboxamide (4.29g, 14.5 mmol) in THF (100 ml) was added methyl magnesiumbromide (18.2ml, 17.4 mmol, 0.96M in THF solution) at 0° C. dropwise and the mixturewas stirred at 0° C. for 1 hour. Then, the mixture was quenched withsaturated ammonium chloride aqueous solution (50 ml) and water (200 ml).After stirring for 30 min, the product was extracted with ethyl acetatewhich was dried over sodium sulfate. Then, filtration, evaporation andpurification through silica gel column chromatography, eluting withhexane/ethyl acetate (4:1), furnished the title compound (3.47 g, 96%yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 2.66 (3H, s),7.83-7.88 (1H, m), 8.02-8.20 (4H, m). MS (ESI): m/z 250, 252 (M+H)⁺.

Step C-5C: 2-(6-Bromoquinolin-2-yl)-1,1,1-trifluoropropan-2-ol

A DMF (5 ml) solution of 1-(6-bromoquinolin-2-yl)ethanone (129 mg, 0.52mmol), (trifluoromethyl)trimethylsilane (220 mg, 1.55 mmol) andtetrabutylammonium fluoride (13.5 mg, 0.052 mmol) was stirred at 100° C.for 2 hours. Then the mixture was cooled to room temperature and1N-hydrochloride aqueous solution (2 ml) was added. After 4 hours, themixture was quenched with saturated sodium bicarbonate aqueous solution,and the product was extracted with ethyl acetate which was dried oversodium sulfate. Then, filtration, evaporation and purification throughsilica gel column chromatography, eluting with hexane/ethyl acetate(4:1), furnished the title compound (175 mg, quant.) as a white solid.¹H NMR (300 MHz, CDCl₃) δ 1.81 (3H, s), 6.51 (1H, s), 7.64 (1H, d, J=8.1Hz), 7.66-7.89 (1H, m), 8.00-8.12 (2H, m), 8.21 (1H, d, J=8.8 Hz). MS(ESI): m/z 320, 322 (M+H)⁺.

Step C-5D: 1-(6-Bromoquinolin-2-yl)-2,2,2-trifluoro-1-methylethylmethanesulfonate

To a solution of of 2-(6-bromoquinolin-2-yl)-1,1,1-trifluoropropan-2-ol(1.93 g, 6.03 mmol) in THF (20 ml) was added sodium hydride (241 mg,7.23 mmol) portionwise at 0° C. and the mixture was stirred at roomtemperature for 1 hour. A solution of methanesulfonyl chloride (829 mg,7.23 mmol) in THF (2 ml) was added at 0°. Then the reaction mixture wasstirred at room temperature for 16 hours. The mixture was quenched withsaturated sodium bicarbonate aqueous solution, and the product wasextracted with ethyl acetate which was dried over sodium sulfate. Then,filtration, evaporation and purification through silica gel columnchromatography, eluting with hexane/ethyl acetate (15:1 to 5:1),furnished the title compound (1.11 g, 46% yield) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 2.45 (3H, s), 3.24 (3H, s), 7.81-7.86 (2H, m),7.96-8.05 (2H, m), 8.17 (1H, d, J=8.8 Hz). MS (ESI): m/z 397, 399(M+H)⁺.

Step C-5E: 6-Bromo-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline

To a suspension of1-(6-bromoquinolin-2-yl)-2,2,2-trifluoro-1-methylethyl methanesulfonate(1.40 g, 3.52 mmol) in cyclohexane (14 ml) was added trimethylaluminum(14 ml, 14 mmol, 1.03M in hexane solution) at room temperature, and themixture was stirred at room temperature for 16 hours. The reaction wascarefully quenched with saturated sodium bicarbonate aqueous solution(10 ml), brine (10 ml) and diluted with ethyl acetate (100 ml). Afterthe mixture was stirred for 30 minutes, formed precipitate was removedby celite and washed with ethyl acetate. The filtrate was concentratedand purified through silica gel column chromatography, eluting withhexane only, to furnish the title compound (951 mg, 85% yield) ascolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 1.72 (6H, s), 7.66 (1H, d,J=8.8 Hz), 7.75-7.80 (1H, m), 7.96-8.00 (2H, m), 8.06 (1H, d, J=8.8 Hz).MS (ESI): m/z 318, 320 (M+H)⁺.

Step C-5F: Methyl2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylate

A mixture of 6-bromo-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline (950mg, 3.0 mmol), triethylamine (1.25 ml, 9.0 mmol),1,3-bis(diphenylphosphino)propane (123 mg, 0.3 mmol), palladium acetate(67 mg, 0.3 mmol) and methanol (4.8 ml) in DMF (10 ml) was stirred atreflux under carbon monoxide (1 atm) for 16 hours. Then the reaction wasquenched with saturated sodium bicarbonate aqueous solution and theproduct was extracted with ethyl acetate which was dried over sodiumsulfate. Then, filtration, evaporation and purification through silicagel column chromatography, eluting with hexane/ethyl acetate (25:1),furnished the title compound (777 mg, 88% yield) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 1.74 (6H, s), 4.00 (3H, s), 7.71 (1H, d, J=8.8Hz), 8.14 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=8.8 Hz), 8.28-8.32 (1H, m),8.58-8.59 (1H, m). MS (ESI): m/z 298 (M+H)⁺.

Step C-5G: 2-(2,2,2-Trifluoro-1,1-dimethylethyl)quinoline-6-carboxylicacid)

A methanol (6 ml) and THF (6 ml) solution of methyl2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylate (777 mg,2.6 mmol) and 2M sodium hydroxide aqueous solution (2.6 ml, 5.2 mmol)was treated in the procedure described in Step C-2C to furnish the titlecompound (735 mg, 99% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.75 (6H, s), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.29 (1H,d, J=8.8 Hz), 8.35-8.40 (1H, m), 8.69-8.70 (1H, m). MS (ESI): m/z 284(M+H)⁺.

Example A16-tert-Butyl-N-[(1R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]-2-naphthamide

To a DMF (30 ml) solution of Amine 4 (100 mg, 0.44 mmol), CarboxylicAcid 1 (73 mg, 0.44 mmol), HBTU (178 mg, 0.47 mmol) and trimethylamine(1 ml) were added and the mixture was stirred for 3 hours at roomtemperature. The reaction was quenched with water and the product wasextracted with EtOAc. Then, evaporation and purification through silicagel column chromatography gave the title compound (72.9 mg, 50%) as awhite solid. ¹H NMR (270 MHz, CDCl₃) δ 1.39 (9H, s), 1.45 (3H, d, J=7.3Hz), 2.11 (3H, s), 3.79 (3H, s), 5.46 (1H, m), 6.97 (1H, s), 7.36 (1H,s), 7.72 (1H, d, J=9.2 Hz), 7.84-8.03 (4H, m), 8.93 (1H, d, J=7.3 Hz).MS (ESI): m/z 410 (M+H)⁺

Example A26-tert-Butyl-N-[(1R)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]-2-naphthamide

To a DCM (10 mL) solution of Example A1 (111 mg, 0.271 mmol) was addedboron tribromide (1.0M solution in DCM, 1.08 ml, 1.08 mmol) at 0° C.under nitrogen, and the resulting mixture was stirred at roomtemperature for 3 hours. The reaction mixture was quenched withsaturated aqueous sodium bicarbonate (30 ml), extracted with DCM (30ml×3 times), and the combined organic layer was dried over sodiumsulfate. Removal of the solvent gave a residue, which waschromatographed on a column of silica gel, eluting with EtOAc-Hexane(1:2 to 1:1), gave the phenol compound of Example A2 (90.4 mg, 84%) aswhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.40 (9H, s), 1.43 (3H, d,J=6.6 Hz), 2.08 (3H, s), 5.42 (1H, m), 6.80 (1H, s), 7.29 (1H, s), 7.72(1H, d, J=8.8 Hz), 7.84-8.03 (4H, m), 8.89 (1 H, d, J=7.3 Hz), 9.67 (1H, s). MS (ESI): m/z 396 (M+H)⁺

Example B16-tert-Butyl-N-(2-chloro-4-hydroxy-5-methylbenzyl)quinoline-2-carboxamide

Example B1 was prepared from Amine A-1 and Caboxylic Acid C-2 by themethod described in Example A1 and Scheme 1. ¹H NMR (270 MHz, CDCl₃) δ1.43 (9H, s), 1.59-1.73 (1H, m), 3.49 (1H, s), 3.84 (3H, s). 4.74 (2H,d, J=6.6 Hz), 5.77-6.02 (1H, m), 6.97 (1H, s), 7.00 (1H, s), 7.78 (1H,d, J=2.0 Hz), 7.85 (1H, dd, J=2.0 Hz, 8.6 Hz), 8.22-8.34 (2H, m), 8:67(1 H, m). MS (ESI): m/z 399 (M+H)⁺, 397 (M−H)⁺

Example C1N-[(1R)-1-(2-Chloro-4-methoxy-5-methylphenyl)ethyl]-7-(trifluoromethyl)quinoline-3-carboxamide

Prepared from Amine A-4 and Carboxylic Acid C-3 by the method describedin Example A1 and Scheme 1. ¹H NMR (270 MHz, CDCl₃) δ 1.67 (3H, d, J=7.3Hz), 2.19 (3H, s), 3.82 (3H, s). 5.56 (1H, m), 6.79 (1H, d, J=7.9 Hz),6.84 (1H, s), 7.17 (1H, s), 7.97 (1H, dd, J=2.0 Hz, 8.6 Hz), 8.16-8.36(2H, m), 8.65 (1H, s), 9.38 (1H, d, J=2.6 Hz). MS (ESI): m/z 423 (M+H)⁺,421 (M−H)⁺

Example C2:N-[(1R)-1-(2-Chloro-4-hydroxy-5-methylphenyl)ethyl]-7-(trifluoromethyl)quinoline-3-carboxamide

Prepared by demethylation of Example C1 by the method described inExample A2 and Scheme 2. ¹H NMR (270 MHz, DMSO-d₆) δ 1.46 (3H, d, J=7.3Hz), 2.10 (3H, s), 5.43 (1H, m), 6.81 (1H, s), 7.31 (1H, s), 8.12 (1H,dd, J=2.0 Hz, 6.6 Hz), 8.31 (1H, d, J=8.6 Hz), 8.66 (1H, s), 9.05 (1H,d, J=2.6 Hz), 9.19 (1H, d, J=7.25 Hz), 9.44 (1H, d, J=2.6 Hz), 9.72 (1H,br s). MS (ESI): m/z 409 (M+H)⁺, 407 (M−H)⁺.

Example D12-tea-Butyl-[(1R)-1-(2-chloro-4-hydroxy-5-methoxyphenyl)ethyl]quinoline-6-carboxamide

Prepared from Amine A-3 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (270 MHz, CDCl₃) δ 1.47 (9H, s), 1.67(3H, d, J=7.3 Hz), 3.88 (3H, s), 5.50 (1H, m), 5.74 (1H, br s), 6.85(1H, d, J=7.9 Hz), 6.90 (1H, s), 6.97 (1H, s), 7.58 (1H, d, J=9.2 Hz),7.99 (1H, dd, J=2.0 Hz, 8.6 Hz), 8.09 (1H, d, J=8.6 Hz), 8.13 (1H, d,J=8.6 Hz), 8.26 (1H, d, J=2.0 Hz). MS (ESI): m/z 413 (M+H)⁺, 411 (M−H)⁺

Example D22-tert-Butyl-N-(2-chloro-4-hydroxy-5-methoxybenzyl)quinoline-6-carboxamide

Prepared from Amine A-1 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (270 MHz, CDCl₃) δ 1.47 (9H, s), 3.89(3H, s), 4.70 (2H, d, J=5.9 Hz), 5.74 (1H, br s), 6.75 (1H, m), 6.98(1H, s), 7.04 (1H, s), 7.59 (1H, d, J=8.6 Hz), 7.99 (1H, dd, J=2.0 Hz,8.6 Hz), 8.09 (1H, d, J=8.6 Hz), 8.14 (1H, d, J=9.2 Hz), 8.24 (1H, s).MS (ESI): m/z 399 (M+H)⁺, 397 (M−H)⁺

Example D3N-(2-Bromo-4-hydroxy-5-methoxybenzyl)-2-tert-butylquinoline-6-carboxamide

Prepared from Amine A-2 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (270 MHz, CDCl₃) δ 1.47 (9H, s), 3.89(3H, s), 4.70 (2H, d, J=5.9 Hz), 5.74 (1H, br s), 6.75 (1H, m), 6.98(1H, s), 7.04 (1H, s), 7.59 (1H, d, J=8.6 Hz), 7.99 (1H, dd, J=2.0 Hz,8.6 Hz), 8.09 (1H, d, J=8.6 Hz), 8.14 (1H, d, J=9.2 Hz), 8.24 (1H, s).MS (ESI): m/z 399 (M+H)⁺, 397 (M−H)⁺

Example D42-tent-Butyl-N-[(1R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]quinoline-6-carboxamide

Prepared from Amine A-4 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.64(3H, d, J=6.6 Hz), 2.17 (3H, s), 3.81 (3H, s), 5.55 (1H, m), 6.78 (1H,m), 6.84 (1H, s), 7.18 (1H, s), 7.57 (1H, d, J=8.8 Hz), 8.01 (1H, dd,J=1.5 Hz, 8.8 Hz), 8.08 (1H, d, J=8.8 Hz), 2.12 (1H, d, J=8.8 Hz), 8.26(1H, d, J=2.2 Hz). MS (ESI): m/z 411 (M+H)⁺, 409 (M−H)⁺

Example D52-tert-butyl-N-[(1R)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]5quinoline-6-carboxamide

Prepared by demethylation of Example D4 by the method described inExample A2 and Scheme 2. ¹H NMR (270 MHz, DMSO-d₆) δ 1.43 (9H, s), 1.44(3H, d, J=6.6 Hz), 2.09 (3H, s), 5.42 (1H, m), 6.80 (1H, s), 7.29 (1H,s), 7.77 (1H, d, J=8.6 Hz), 8.00 (1H, d, J=8.6 Hz), 8.17 (1H, d, J=8.6Hz), 8.40 (1H, d, J=8.6 Hz), 8.50 (1H, s), 8.95 (1H, d, J=7.9 Hz), 9.66(1 H, br s). MS (ESI): m/z 397 (M+H)⁺, 395 (M−H)⁺

Example D62-tert-butyl-N-[(1S)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]quinoline-6-carboxamide

Prepared from Amine A-5 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.64(3H, d, J=6.6 Hz), 2.17 (3H, s), 3.81 (3H, s), 5.55 (1H, m), 6.78 (1H,m), 6.84 (1H, s), 7.18 (1H, s), 7.57 (1H, d, J=8.8 Hz), 8.01 (1H, dd,J=1.5 Hz, 8.8 Hz), 8.08 (1H, d, J=8.8 Hz), 8.12 (1H, d, J=8.8 Hz), 8.26(1 H, d, J=2.2 Hz). MS (ESI): m/z 411 (M+H)⁺, 409 (M−H)⁺

Example D7

2-tert-Butyl-N-[(1S)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]quinoline-6-carboxamide

Prepared by demethylation of Example D6 by the method described inExample A2 and Scheme 2, ¹H NMR (270 MHz, DMSO-d₆) δ 1.43 (9H, s), 1.44(3H, d, J=6.6 Hz), 2.09 (3H, s), 5.42 (1H, m), 6.80 (1H, s), 7.29 (1H,s), 7.77 (1H, d, J=8.6 Hz), 8.00 (1H, d, J=8.6 Hz), 8.17 (1H, d, J=8.6Hz), 8.40 (1H, d, J=8.6 Hz), 8.50 (1H, s), 8.95 (1H, d, J=7.9 Hz), 9.66(1H, br s). MS (ESI): m/z 397 (M+H)⁺, 395 (M−H)⁺

Example D82-tert-Butyl-N-{(1R)-1-[4-(hydroxymethyl)phenyl]ethyl}quinoline-6-carboxamide

Prepared from Amine A-8 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (300 MHz, DMSO) δ1.42 (9H, s), 1.51(3H, d, J=6.6 Hz), 4.46 (2H, d, J=5.9 Hz), 5.12 (1H, t, J=5.9 Hz),5.18-5.26 (1H, m), 7.27 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=7.3 Hz), 7.75(1H, d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.14-8.18 (1H, m), 8.40 (1H,d, J=8.8 Hz), 8.49-8.50 (1H, m), 9.00 (1H, d, J=8.1 Hz). MS (ESI): m/z363 (M+H)+.

Example D92-tert-Butyl-N-(2-chloro-4-methoxy-5-methylbenzyl)quinoline-6-carboxamide

Prepared from Amine A-7 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (270 MHz, DMSO-d₆) δ 1.43 (9H, s),2.10 (3H, s), 3.81 (3H, s), 4.52 (2H, d, J=5.9 Hz), 7.03 (1 H, s), 7.21(1 H, s), 7.76 (1 H, d, J=8.6 Hz), 8.01 (1H, d, J=8.6 Hz), 8.19 (1H, dd,J=2.0 Hz, 9.2 Hz), 8.40 (1H, d, J=8.6 Hz), 8.52 (1H, s), 9.10 (1H, m).MS (ESI): m/z 397 (M+H)⁺, 395 (M−H)⁺

Example D102-tert-Butyl-N-(2-chloro-4-hydroxy-5-methylbenzyl)quinoline-6-carboxamide

Prepared by demethylation of Example D9 by the method described inExample A2 and Scheme 2. ¹H NMR (270 MHz, DMSO-d₆) δ 1.43 (9H, s), 2.08(3H, s), 4.47 (2H, d, J=5.9 Hz), 6.84 (1H, s), 7.14 (1H, s), 7.76 (1H,d, J=8.6 Hz), 8.00 (1H, d, J=8.6 Hz), 8.18 (1H, d, J=8.6 Hz), 8.39 (1H,d, J=8.6 Hz), 8.51 (1H, s), 9.04 (1H, m), 8.73 (1H, br s).

MS (ESI): m/z 383 (M+H)⁺, 381 (M−H)⁺

Example D112-tert-Butyl-N-(2-fluoro-4-hydroxy-5-methylbenzyl)quinoline-6-carboxamide

Prepared from Amine A-6 and Carboxylic acid C-4 by the method describedin Example A1 and Scheme 1. ¹H NMR (300 MHz, DMSO-d₆) δ1.42 (9H, s),2.06 (3H, s), 4.42-4.45 (2H, m), 6.57 (1H, d, J=11.0 Hz), 7.11 (1H, d,J=8.8 Hz), 7.76 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.17 (1H, d,J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz), 8.49 (1H, s), 9.05 (1H, brs), 9.70(1H, brs). MS (ESI): m/z 367 (M+H)+.

Example D12N-[(1R)-1-(2-Chloro-4-methoxy-5-methylphenyl)ethyl]-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxamide

Prepared from Amine A-4 and Carboxylic acid C-5 by the method describedin Example A1 and Scheme 1. ¹H NMR (300 MHz, DMSO-d₆) δ1.46 (3H, d,J=6.6 Hz), 1.72 (6H, s), 2.11 (3H, s), 3.79 (3H, s), 5.44-5.48 (1H, m),6.98 (1H, s), 7.37 (1H, s), 7.88 (1H, d, J=8.1 Hz), 8.09 (1H, d, J=8.8Hz), 8.24 (1H, d, J=8.8 Hz), 8.54-8.59 (2H, m), 9.08 (1H, d, J=8.1 Hz).MS (ESI): m/z 465 (M+H)+.

Example D13N-[(1R)-1-(2-Chloro-4-hydroxy-5-methylphenyl)ethyl]-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxamide

Prepared by demethylation of Example D12 by the method described inExample A2 and Scheme 2. ¹H NMR (300 MHz, DMSO-d₆) δ1.44 (3H, d, J=6.6Hz), 1.72 (6H, s), 2.08 (3H, s), 5.40-5.44 (1H, m), 6.80 (1H, s), 7.29(1H, s), 7.89 (1H, d, J=8.8 Hz), 8.09 (1H, d, J=8.8 Hz), 8.22-8.24 (1H,m), 8.53-8.57 (2H, m), 9.03 (1H, d, J=7.3 Hz), 9.70 (1H, brs).

MS (ESI): m/z 451 (M+H)+.

Example D14N-{1-[2-Fluoro-4-(hydroxymethyl)-5-methylphenyl]ethyl}-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxamide

Prepared from Amine A-9 and Carboxylic Acid C-5 by the method describedin Example A1 and Scheme 1. ¹H NMR (300 MHz, DMSO-d₆) δ 1.50 (3H, d,J=7.3 Hz), 1.72 (6H, s), 2.17 (3H, s), 4.44 (2H, d, J=5.1 Hz), 5.21 (1H,t, J=5.1 Hz), 5.38-5.46 (1H, m), 7.12 (1H, d, J=11.7 Hz), 7.26 (1H, d,J=8.1 Hz), 7.89 (1H, d, J=8.8 Hz), 8.09 (1H, d, J=8.8 Hz), 8.23 (1H, d,J=9.5 Hz), 8.54-8.59 (2H, m), 9.08 (1H, d, J=7.3 Hz). MS (ESI): m/z 449(M+H)+.

Example D152-tert-Butyl-N-[(1R)-1-(4-hydroxy-3-methoxyphenyl)ethyl]quinoline-6-carboxamide

Prepared from Amine 10 and Carboxylic Acid 4 by the method described inExample A1 and Scheme 1. ¹H NMR (270 MHz,CDCl₃) δ 1.47 (9H, s), 1.63(3H, d, J=7.3 Hz), 3.88 (3H, s), 5.33 (1 H, m), 5.85 (1 H, brs), 6.60 (1H, m), 6.85-7.00 (3H, m), 7.57 (1H, d, J=8.6 Hz), 7.90-8.15 (3H, m),8.25 (1H, s). MS (ESI): m/z 379 (M+H)⁺, 377 (M−H)⁺.

1. A compound of the formula (I):

wherein Y¹ and Y² are each independently CH or N, Y³ is CR³ or N, withthe proviso that only one of Y¹, Y² and Y³ is N; R¹ and R² are eachindependently hydrogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl orhydroxy(C₁-C₆)alkyl; R³ is hydrogen, halogen, hydroxy, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C₁-C₆)alkoxy or halo(C₁-C₆)alkyl; R⁴ is halogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy-(C₁-C₆)alkoxy, halo(C₁-C₆)alkylsulfonyl,halo(C₁-C₆)alkylsulfinyl, halo(C₁-C₆)alkylthio, [(C₁-C₆)alkyl]NH—,[(C₁-C₆)alkyl]₂N—, azetidinyl, pyrrolidinyl or piperidinyl; R⁶ is,hydroxy, hydroxy(C₁-C₆)alkyl, or (C₁-C₆)alkoxy; R⁵ is hydrogen, halogen,hydroxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or (C₁-C₆)alkoxy; R⁷ ishydrogen, halogen, hydroxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, or(C₁-C₆)alkoxy; R⁸ is hydrogen, halogen, (C₁-C₆)alkyl orhalo(C₁-C₆)alkyl; or a pharmaceutically acceptable salt or solvatethereof.
 2. A compound according to claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y¹ is N, Y² is CH and Y³ isCH.
 3. A compound according to claim 1, or a pharmaceutically acceptablesalt or solvate thereof, wherein Y¹ is CH, Y² is N and Y³ is CH.
 4. Acompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein Y¹ is CH, Y² is CH, Y³ is N.
 5. A compoundaccording to claim 1, or a pharmaceutically acceptable salt or solvatethereof, wherein Y¹ is CH, Y² is CH, Y³ is CH.
 6. A compound accordingto claim 4, or a pharmaceutically acceptable salt or solvate thereof,wherein R¹ and R² are each independently hydrogen or (C₁-C₆)alkyl.
 7. Acompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹ is hydrogen or methyl and R² is hydrogen. 8.A compound according to claim 1, or a pharmaceutically acceptable saltor solvate thereof, wherein R¹ is methyl and R² is hydrogen.
 9. Acompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein R³ is hydrogen.
 10. A compound according toclaim 4, or a pharmaceutically acceptable salt or solvate thereof,wherein R⁴ is (C₁-C₆)alkyl or halo(C₁-C₆)alkyl.
 11. A compound accordingto claim 1, or a pharmaceutically acceptable salt or solvate thereof,wherein R⁴ is tert-butyl, trifluoromethyl or2,2,2-trifluoro-1,1-dimethyl-ethyl.
 12. A compound according to claim 1,or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶ ishydroxy, hydroxymethyl or methoxy.
 13. A compound according to claim 4,or a pharmaceutically acceptable salt or solvate thereof, wherein R⁷ isselected from hydrogen, halogen, hydroxy, (C₁-C₆)alkyl or (C₁-C₆)alkoxy.14. A compound according to claim 4, or a pharmaceutically acceptablesalt or solvate thereof, wherein R⁷ is hydrogen or halogen.
 15. Acompound according to claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein R⁷ is hydrogen, fluoro, chloro or bromo.
 16. Acompound according to claim 4, or a pharmaceutically acceptable salt orsolvate thereof, wherein R⁵ is selected from hydrogen, halogen, hydroxy,(C₁-C₆)alkyl or (C₁-C₆)alkoxy.
 17. A compound according to claim 1, or apharmaceutically acceptable salt or solvate thereof, wherein R⁵ ishydrogen, methyl or methoxy.
 18. A compound according to claim 1, or apharmaceutically acceptable salt or solvate thereof, said compound beingselected from,6-tert-butyl-N-[(1R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]-2-naphthamide;6-tent-butyl-N-[(1R)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]-2-naphthamide;6-tert-butyl-N-(2-chloro-4-hydroxy-5-methylbenzyl)quinoline-2-carboxamide;N-[(1R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]-7-(trifluoromethyl)quinoline-3-carboxamide;N-[(1R)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]-7-(trifluoromethyl)quinoline-3-carboxamide;2-tert-butyl-N-[(1R)-1-(2-chloro-4-hydroxy-5-methoxyphenyl)ethyl]quinoline-6-carboxamide;2-tert-butyl-N-(2-chloro-4-hydroxy-5-methoxybenzyl)quinoline-6-carboxamide;N-(2-bromo-4-hydroxy-5-methoxybenzyl)-2-tert-butylquinoline-6-carboxamide;2-tent-butyl-N-[(1R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]quinoline-6-carboxamide;2-tert-butyl-N-[(1R)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]quinoline-6-carboxamide;2-tert-butyl-N-[(1S)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]quinoline-6-carboxamide;2-tert-butyl-N-[(1S)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]quinoline-6-carboxamide;2-tert-butyl-N-{(1R)-1-[4-(hydroxymethyl)phenyl]ethyl}quinoline-6-carboxamide;2-tert-butyl-N-(2-chloro-4-methoxy-5-methylbenzyl)quinoline-6-carboxamide;2-tert-butyl-N-(2-chloro-4-hydroxy-5-methylbenzyl)quinoline-6-carboxamide;2-tert-butyl-N-(2-fluoro-4-hydroxy-5-methylbenzyl)quinoline-6-carboxamide;N-[(1R)-1-(2-chloro-4-methoxy-5-methylphenyl)ethyl]-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxamide;N-[(1R)-1-(2-chloro-4-hydroxy-5-methylphenyl)ethyl]-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxamide;N-{1-[2-fluoro-4-(hydroxymethyl)-5-methylphenyl]ethyl}-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxamide;and,2-tert-butyl-N-[(1R)-1-(4-hydroxy-3-methoxyphenyl)ethyl]quinoline-6-carboxamide.19. (canceled)
 20. A pharmaceutical composition including a compound ofthe formula (I) or a pharmaceutically acceptable salt or solvatethereof, as defined in claim 1, together with a pharmaceuticallyacceptable excipient.
 21. (canceled)
 22. (canceled)
 23. A method oftreatment of a mammal for a disease for which a VR1 antagonist isindicated, including treating said mammal with an effective amount of acompound of the formula (I) or with a pharmaceutically acceptable saltor solvate thereof, as defined in claim
 1. 24. (canceled)
 25. Apharmaceutical composition including a compound of the formula (I) or apharmaceutical acceptable salt as defined in claim 1, and anotherpharmacologically active agent.
 26. A method of treating pain, chronicpain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain,post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy,HIV-related neuropathy, nerve injury, rheumatoid arthritic pain,osteoarthritic pain, burns, back pain, visceral pain, cancer pain,dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia,neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrualpain, bladder disease, urinary incontinence, lower urinary tractsymptoms, micturition disorder, renal colic, cystitis, inflammation,burns, rheumatoid arthritis, osteoarthritis, neurodegenerative disease,stroke, post stroke pain, multiple sclerosis, diseases of therespiratory tree that have a contribution to symptoms or pathologyarising from the sensory afferent nervous system, cough,bronchoconstriction, irritation, inflammation of the lower airway,asthma, COPD, allergic rhinitis, chronic sinusitis, gastrointestinaldisorders, gastroesophageal reflux disease, dysphagia, ulcer, irritablebowel syndrome, inflammatory bowel disease, colitis, Crohn's disease,ischemia, cerebrovascular ischemia, acute cerebral ischemia, emesis,cancer chemotherapy-induced emesis, diabetes and obesity in a mammalcomprising treating said mammal with an effective amount of a compoundof the formula (I) or with a pharmaceutically acceptable salt or solvatethereof, as defined in claim 1.